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Song Z, Cui Y, Xin L, Xiao R, Feng J, Li C, Yin Z, Wang H, Li Q, Wang M, Lin B, Zhang Y, Zhou Y, Huang L, He Y, Li X, Liu X, Liu S, Zhou F, Liu Z, Zhou HB, Fang P, Liang K. Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation. Cell Stem Cell 2025; 32:581-597.e11. [PMID: 39986274 DOI: 10.1016/j.stem.2025.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/12/2024] [Accepted: 01/25/2025] [Indexed: 02/24/2025]
Abstract
Mitochondria are integrated within the cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20-PDH+mtDNA+ mitochondrial-derived vesicles that activate cGAS-STING signaling, with Sting knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.
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Affiliation(s)
- Zemin Song
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yali Cui
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Lilan Xin
- State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Ruijing Xiao
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Jingjing Feng
- The Institute for Advanced Studies, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Conghui Li
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Zhinang Yin
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Honghong Wang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Qiuzi Li
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Mengxuan Wang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Baoyi Lin
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yiming Zhang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Ying Zhou
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Li Huang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yanli He
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoqing Li
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoyan Liu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shangqin Liu
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Zheng Liu
- The Institute for Advanced Studies, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Hai-Bing Zhou
- State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
| | - Pingping Fang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
| | - Kaiwei Liang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
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Ragazzini G, Mescola A, Tassinari R, Gallerani A, Zannini C, Di Rosa D, Cavallini C, Marcuzzi M, Taglioli V, Bighi B, Ettari R, Zappavigna V, Ventura C, Alessandrini A, Corsi L. A Benzodiazepine-Derived Molecule That Interferes with the Bio-Mechanical Properties of Glioblastoma-Astrocytoma Cells Altering Their Proliferation and Migration. Int J Mol Sci 2025; 26:2767. [PMID: 40141408 PMCID: PMC11943291 DOI: 10.3390/ijms26062767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Glioblastoma multiforme (grade IV glioma) is characterized by a high invasive potential, making surgical intervention extremely challenging and patient survival very limited. Current pharmacological approaches show, at best, slight improvements in the therapy against this type of tumor. Microtubules are often the target of antitumoral drugs, and specific drugs affecting their dynamics by acting on microtubule-associated proteins (MAPs) without producing their depolymerization could affect both glioma cell migration/invasion and cell proliferation. Here, we analyzed on a cellular model of glioblastoma multiforme, the effect of a molecule (1-(4-amino-3,5-dimethylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4h2,3-benzodiazepin-4-one, hereafter named 1g) which was shown to act as a cytostatic drug in other cell types by affecting microtubule dynamics. We found that the molecule acts also as a migration suppressor by inducing a loss of cell polarity. We characterized the mechanics of U87MG cell aggregates exposed to 1g by different biophysical techniques. We considered both 3D aggregates and 2D cell cultures, testing substrates of different stiffness. We established that this molecule produces a decrease of cell spheroid contractility and it impairs 3D cell invasion. At the same time, in the case of isolated cells, 1g selectively produces an almost instantaneous loss of cell polarity blocking migration and it also produces a disorganization of the mitotic spindle when cells reach mitosis, leading to frequent mitotic slippage events followed by cell death. We can state that the studied molecule produces similar effects to other molecules that are known to affect the dynamics of microtubules, but probably indirectly via microtubule-associated proteins (MAPs) and following different biochemical pathways. Consistently, we report evidence that, regarding its effect on cell morphology, this molecule shows a specificity for some cell types such as glioma cells. Interestingly, being a molecule derived from a benzodiazepine, the 1g chemical structure could allow this molecule to easily cross the blood-brain barrier. Thanks to its chemical/physical properties, the studied molecule could be a promising new drug for the specific treatment of GBM.
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Affiliation(s)
- Gregorio Ragazzini
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Andrea Mescola
- CNR-Nanoscience Institute-S3, Via Campi 213/A, 41125 Modena, Italy;
| | - Riccardo Tassinari
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Alessia Gallerani
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
| | - Chiara Zannini
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Domenico Di Rosa
- Lab of Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, SaIA, University of Salerno, 84081 Baronissi, Italy;
| | - Claudia Cavallini
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Martina Marcuzzi
- Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 49, 40126 Bologna, Italy;
| | - Valentina Taglioli
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
| | - Beatrice Bighi
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
- CNR-Nanoscience Institute-S3, Via Campi 213/A, 41125 Modena, Italy;
| | - Roberta Ettari
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98168 Messina, Italy;
| | - Vincenzo Zappavigna
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy;
| | - Carlo Ventura
- Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy; (R.T.); (C.Z.); (C.C.); (V.T.); (C.V.)
- Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 49, 40126 Bologna, Italy;
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy
| | - Andrea Alessandrini
- Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Via Campi 213/A, 41125 Modena, Italy; (G.R.); (A.G.); (B.B.)
- CNR-Nanoscience Institute-S3, Via Campi 213/A, 41125 Modena, Italy;
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy
| | - Lorenzo Corsi
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy;
- National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems, Eldor Lab, Via di Corticella 183, 40128 Bologna, Italy
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Pan Y, Liu Q, Li Q, Ren Z. Mechanistic insights into Uc001kfo-induced hepatocellular carcinoma metastasis. Discov Oncol 2025; 16:260. [PMID: 40025303 PMCID: PMC11872824 DOI: 10.1007/s12672-025-02000-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/19/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Previous studies have identified the long non-coding RNA (lncRNA) Uc001kfo as significantly upregulated in hepatocellular carcinoma (HCC) tissues, particularly in advanced stages, compared to adjacent non-cancerous tissues. This study aims to further explore the molecular mechanisms by which Uc001kfo promotes HCC metastasis, focusing on its regulation of α-SMA expression. METHODS The study investigate the effects of Uc001kfo on proliferation, migration, and invasion in HCC cells using in vitro assays. Additionally, we also explored the molecular mechanism by which Uc001kfo indirectly regulates α-SMA gene transcription through its targeting of Sp1. Finally, we conducted preliminary validation in mice model to assess the potential for Uc001kfo-targeted silencing to inhibit HCC cell invasion and metastasis. RESULTS The results of the study demonstrate that the Uc001kfo/Sp1/α-SMA pathway plays a role in regulating HCC metastasis. Uc001kfo inhibits the degradation of Sp1 protein, thereby promoting Sp1 binding to the α-SMA promoter and enhancing its transcription. Consequently, silencing Uc001kfo can indirectly suppress α-SMA expression, effectively inhibiting HCC cell proliferation, invasion, and migration in vitro, as well as liver metastasis in mice through the spleen. CONCLUSION Uc001kfo plays a critical role in promoting HCC metastasis, making it a potential a promising therapeutic target for inhibiting tumor progression and metastasis in HCC.
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Affiliation(s)
- Yanfeng Pan
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Wulibao Street, Zhengzhou, Henan, China.
| | - Qin Liu
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Qingqing Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Wulibao Street, Zhengzhou, Henan, China
| | - Zhenjun Ren
- Department of Emergency, The Shanghai Deji Hospital, 378# Gulang Road, Shanghai, China.
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Wu M, Yang H, Liu S, Jiang L, Liang T, Wang Y, Zhu M, Song X, Liu H, Shen J, Wang S, Zhu X, Qu CK, Cheng L, Jiang H, Ni F. Enhanced engraftment of human haematopoietic stem cells via mechanical remodelling mediated by the corticotropin-releasing hormone. Nat Biomed Eng 2024:10.1038/s41551-024-01316-1. [PMID: 39715892 DOI: 10.1038/s41551-024-01316-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/01/2024] [Indexed: 12/25/2024]
Abstract
The engraftment of haematopoietic stem and progenitor cells (HSPCs), particularly in cord-blood transplants, remains challenging. Here we report the role of the corticotropin-releasing hormone (CRH) in enhancing the homing and engraftment of human-cord-blood HSPCs in bone marrow through mechanical remodelling. By using microfluidics, intravital two-photon imaging and long-term-engraftment assays, we show that treatment with CRH substantially enhances HSPC adhesion, motility and mechanical remodelling, ultimately leading to improved bone-marrow homing and engraftment in immunodeficient mice. CRH induces Ras homologue gene family member A (RhoA)-dependent nuclear translocation of the yes-associated protein (YAP), which upregulates the expression of genes encoding extracellular-matrix proteins (notably, thrombospondin-2 (THBS2)). This process guides the mechanical remodelling of HSPCs via modulation of the actin cytoskeleton and the extracellular matrix, with THBS2 interacting with the integrin αvβ3 and coordinating the nuclear translocation of YAP upon CRH/CRH-receptor-1 (CRH/CRHR1) signalling. Overall, the CRH/CRHR1/RhoA/YAP/THBS2/αvβ3 axis has a central role in modulating HSPC behaviour via a mechanical feedback loop involving THBS2, αvβ3, the actin cytoskeleton and YAP signalling. Our findings may suggest avenues for optimizing the transplantation of HSPCs.
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Affiliation(s)
- Mingming Wu
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haoxiang Yang
- The CAS Key Laboratory of Mechanical Behavior and Design of Materials, University of Science and Technology of China, Hefei, China
| | - Senquan Liu
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lai Jiang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Tingting Liang
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yan Wang
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mingming Zhu
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xian Song
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hao Liu
- The CAS Key Laboratory of Mechanical Behavior and Design of Materials, University of Science and Technology of China, Hefei, China
| | - Jinghao Shen
- The CAS Key Laboratory of Mechanical Behavior and Design of Materials, University of Science and Technology of China, Hefei, China
| | - Shuangzi Wang
- The CAS Key Laboratory of Mechanical Behavior and Design of Materials, University of Science and Technology of China, Hefei, China
| | - Xiaoyu Zhu
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Cheng-Kui Qu
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Linzhao Cheng
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
| | - Hongyuan Jiang
- The CAS Key Laboratory of Mechanical Behavior and Design of Materials, University of Science and Technology of China, Hefei, China.
| | - Fang Ni
- Department of Hematology, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Blood and Cell Therapy and Anhui Provincial Key Laboratory of Blood Research and Applications, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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Wang F, Yin J, Wang X, Zhang H, Song Y, Zhang X, Wang T. Exposure to trichloromethane via drinking water promotes progression of colorectal cancer by activating IRE1α/XBP1 pathway of endoplasmic reticulum stress. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 949:175040. [PMID: 39079638 DOI: 10.1016/j.scitotenv.2024.175040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/08/2024] [Accepted: 07/23/2024] [Indexed: 08/09/2024]
Abstract
Trichloromethane (TCM), a commonly recognized disinfection by-product formed during the chlorination of water, has been associated with the onset of colorectal cancer (CRC) in humans. Despite this, the impact of TCM on the progression of CRC remains uncertain. In this investigation, it was observed that exposure to TCM could augment the migratory capabilities of CRC cells and facilitate the advancement of colorectal tumors. To delve deeper into the mechanism responsible for TCM-induced CRC progression, we performed RNA-Seq analysis at cellular and animal levels after TCM exposure. Both the KEGG and GO enrichment analyses indicated the activation of endoplasmic reticulum stress (ERS) and the regulation of the cytoskeleton. Subsequently, we confirmed the activation of the IRE1α/XBP1 pathway of ERS through western blot and RT-qPCR. Additionally, we observed the aggregation of cytoskeletal proteins F-actin and β-tubulin at the cell membrane periphery and the development of cellular pseudopods using immunofluorescence following exposure to TCM in vitro. The downregulation of IRE1α and XBP1 through siRNA interference resulted in the disruption of cell cytoskeleton rearrangement and impaired cell migration capability. Conversely, treatment with TCM mitigated this inhibitory effect. Moreover, chronic exposure to low concentration of TCM also triggered CRC cell migration by causing cytoskeletal reorganization, a process controlled by the IRE1α/XBP1 axis. Our study concludes that TCM exposure induces cell migration through the activation of ERS, which in turn regulates cytoskeleton rearrangement. This study offers novel insights into the mechanism through which TCM facilitates the progression of CRC.
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Affiliation(s)
- Fan Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China
| | - Jinbao Yin
- Key Laboratory of Integrated Regulation and Resources Development on Shallow Lakes of Ministry of Education, College of Environment, Hohai University, Nanjing, China; State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Xianlin Campus, 163 Xianlin Avenue, Nanjing, China
| | - Xiaochang Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China
| | - Hailing Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China
| | - Yuechi Song
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China
| | - Xuxiang Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Xianlin Campus, 163 Xianlin Avenue, Nanjing, China.
| | - Ting Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, China.
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Chang CY, Pearce G, Betaneli V, Kapustsenka T, Hosseini K, Fischer-Friedrich E, Corbeil D, Karbanová J, Taubenberger A, Dahncke B, Rauner M, Furesi G, Perner S, Rost F, Jessberger R. The F-actin bundler SWAP-70 promotes tumor metastasis. Life Sci Alliance 2024; 7:e202302307. [PMID: 38760173 PMCID: PMC11101836 DOI: 10.26508/lsa.202302307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/19/2024] Open
Abstract
Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for understanding metastasis and potential therapies. We hypothesized that the unique F-actin binding and bundling protein SWAP-70 contributes importantly to metastasis. Orthotopic, ectopic, and short-term tail vein injection mouse breast and lung cancer models revealed a strong positive dependence of lung and bone metastasis on SWAP-70. Breast cancer cell growth, migration, adhesion, and invasion assays revealed SWAP-70's key role in these metastasis-related cell features and the requirement for SWAP-70 to bind F-actin. Biophysical experiments showed that tumor cell stiffness and deformability are negatively modulated by SWAP-70. Together, we present a hitherto undescribed, unique F-actin modulator as an important contributor to tumor metastasis.
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Affiliation(s)
- Chao-Yuan Chang
- Institute for Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Glen Pearce
- Institute for Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Viktoria Betaneli
- Institute for Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Tatsiana Kapustsenka
- Institute for Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Kamran Hosseini
- Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden, Germany
| | | | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Dresden, Germany
- Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jana Karbanová
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Dresden, Germany
- Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Anna Taubenberger
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Dresden, Germany
- Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Björn Dahncke
- Institute for Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III and Center for Healthy Aging, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Giulia Furesi
- Department of Medicine III and Center for Healthy Aging, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Sven Perner
- Institute of Pathology, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany
- Institute of Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Fabian Rost
- DRESDEN-concept Genome Center, Technology Platform at the Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
| | - Rolf Jessberger
- Institute for Physiological Chemistry, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Tan C, Qin G, Wang QQ, Li KM, Zhou YC, Yao SK. Comprehensive serum proteomics profiles and potential protein biomarkers for the early detection of advanced adenoma and colorectal cancer. World J Gastrointest Oncol 2024; 16:2971-2987. [PMID: 39072170 PMCID: PMC11271786 DOI: 10.4251/wjgo.v16.i7.2971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/08/2024] [Accepted: 05/15/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND The majority of colorectal cancer (CRC) cases develop from precursor advanced adenoma (AA). With the development of proteomics technologies, blood protein biomarkers have potential applications in the early screening of AA and CRC in the general population. AIM To identify serum protein biomarkers for the early screening of AA and CRC. METHODS We collected 43 serum samples from 8 normal controls (NCs), 19 AA patients and 16 CRC patients at China-Japan Friendship Hospital. Quantitative proteomic analysis was performed using liquid chromatography-mass spectrometry/mass spectrometry and data independent acquisition, and differentially expressed proteins (DEPs) with P-values < 0.05 and absolute fold changes > 1.5 were screened out, followed by bioinformatics analysis. Prognosis was further analyzed based on public databases, and proteins expression in tissues were validated by immunohistochemistry. RESULTS A total of 2132 proteins and 17365 peptides were identified in the serum samples. There were 459 upregulated proteins and 118 downregulated proteins in the NC vs AA group, 289 and 180 in the NC vs CRC group, and 52 and 248 in the AA vs CRC group, respectively. Bioinformatic analysis revealed that these DEPs had different functions and participated in extensive signaling pathways. We also identified DIAPH1, VASP, RAB11B, LBP, SAR1A, TUBGCP5, and DOK3 as important proteins for the progression of AA and CRC. Furthermore, VASP (P < 0.01), LBP (P = 0.01), TUBGCP5 (P < 0.01), and DOK3 (P < 0.01) were associated with a poor prognosis. In addition, we propose that LBP and VASP may be more promising protein biomarkers for the early screening of colorectal tumors. CONCLUSION Our study elucidated the serum proteomic profiles of AA and CRC patients, and the identified proteins, such as LBP and VASP, may contribute to the early detection of AA and CRC.
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Affiliation(s)
- Chang Tan
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Qian-Qian Wang
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Kai-Min Li
- School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| | - Yuan-Chen Zhou
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Shu-Kun Yao
- Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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8
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Baro L, Almhassneh RA, Islam A, Juanes MA. Tumor invasiveness is regulated by the concerted function of APC, formins, and Arp2/3 complex. iScience 2024; 27:109687. [PMID: 38680662 PMCID: PMC11053316 DOI: 10.1016/j.isci.2024.109687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/23/2024] [Accepted: 04/05/2024] [Indexed: 05/01/2024] Open
Abstract
Tumor cell invasion is the initial step in metastasis, the leading cause of death from cancer. Invasion requires protrusive cellular structures that steer the migration of leader cells emanating from the tumor mass toward neighboring tissues. Actin is central to these processes and is therefore the prime target of drugs known as migrastatics. However, the broad effects of general actin inhibitors limit their therapeutic use. Here, we delineate the roles of specific actin nucleators in tuning actin-rich invasive protrusions and pinpoint potential pharmacological targets. We subject colorectal cancer spheroids embedded in collagen matrix-a preclinical model mirroring solid tumor invasiveness-to pharmacologic and/or genetic treatment of specific actin arrays to assess their roles in invasiveness. Our data reveal coordinated yet distinct involvement of actin networks nucleated by adenomatous polyposis coli, formins, and actin-related protein 2/3 complex in the biogenesis and maintenance of invasive protrusions. These findings may open avenues for better targeted therapies.
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Affiliation(s)
- Lautaro Baro
- Cytoskeletal Dynamics in Cell Migration and Cancer Invasion Laboratory, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
- School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK
- National Horizons Centre, Teesside University, Darlington DL1 1HG, UK
| | - Rabeah A. Almhassneh
- Cytoskeletal Dynamics in Cell Migration and Cancer Invasion Laboratory, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
| | - Asifa Islam
- School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK
- National Horizons Centre, Teesside University, Darlington DL1 1HG, UK
| | - M. Angeles Juanes
- Cytoskeletal Dynamics in Cell Migration and Cancer Invasion Laboratory, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
- School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK
- National Horizons Centre, Teesside University, Darlington DL1 1HG, UK
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9
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Yang D, Dang S, Wang Z, Xie M, Li X, Ding X. Vessel co-option: a unique vascular-immune niche in liver cancer. Front Oncol 2024; 14:1386772. [PMID: 38737903 PMCID: PMC11082301 DOI: 10.3389/fonc.2024.1386772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 04/11/2024] [Indexed: 05/14/2024] Open
Abstract
Tumor vasculature is pivotal in regulating tumor perfusion, immune cell infiltration, metastasis, and invasion. The vascular status of the tumor is intricately linked to its immune landscape and response to immunotherapy. Vessel co-option means that tumor tissue adeptly exploits pre-existing blood vessels in the para-carcinoma region to foster its growth rather than inducing angiogenesis. It emerges as a significant mechanism contributing to anti-angiogenic therapy resistance. Different from angiogenic tumors, vessel co-option presents a distinctive vascular-immune niche characterized by varying states and distribution of immune cells, including T-cells, tumor-associated macrophages, neutrophils, and hepatic stellate cells. This unique composition contributes to an immunosuppressive tumor microenvironment that is crucial in modulating the response to cancer immunotherapy. In this review, we systematically reviewed the evidence and molecular mechanisms of vessel co-option in liver cancer, while also exploring its implications for anti-angiogenic drug resistance and the immune microenvironment, to provide new ideas and clues for screening patients with liver cancer who are effective in immunotherapy.
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Affiliation(s)
| | | | | | | | | | - Xiangming Ding
- Department of Gastroenterology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
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10
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Göbel C, Schoof M, Holdhof D, Spohn M, Schüller U. SMARCA4 Loss and Mutated β-Catenin Induce Proliferative Lesions in the Murine Embryonic Cerebellum. J Neurosci 2024; 44:e1605232024. [PMID: 38383496 PMCID: PMC11007475 DOI: 10.1523/jneurosci.1605-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/23/2024] Open
Abstract
Almost all medulloblastomas (MB) of the Wingless/Int-1 (WNT) type are characterized by hotspot mutations in CTNNB1, and mouse models have convincingly demonstrated the tumor-initiating role of these mutations. Additional alterations in SMARCA4 are detected in ∼20% of WNT MB, but their functional role is mostly unknown. We, therefore, amended previously described brain lipid binding protein (Blbp)-cre::Ctnnb1(ex3)fl/wt mice by the introduction of floxed Smarca4 alleles. Unexpectedly, mutated and thereby stabilized β-catenin on its own induced severe developmental phenotypes in male and female Blbp-cre::Ctnnb1(ex3)fl/wt mice in our hands, including a thinned cerebral cortex, hydrocephalus, missing cerebellar layering, and cell accumulations in the brainstem and cerebellum. An additional loss of SMARCA4 even resulted in prenatal death for most mice. Respective Blbp-cre::Ctnnb1(ex3)fl/wt::Smarca4fl/rec mutants (male and female) developed large proliferative lesions in the cerebellum evolving from E13.5 to E16.5. Histological and molecular analysis of these lesions by DNA methylation profiling and single-cell RNA sequencing suggested an origin in early undifferentiated SOX2-positive cerebellar progenitors. Furthermore, upregulated WNT signaling, altered actin/cytoskeleton organization, and reduced neuronal differentiation were evident in mutant cells. In vitro, cells harboring alterations in both Ctnnb1 and Smarca4 were negatively selected and did not show tumorigenic potential after transplantation in adult female recipient mice. However, in cerebellar explant cultures, mutant cells displayed significantly increased proliferation, suggesting an important role of the embryonic microenvironment in the development of lesions. Altogether, these results represent an important first step toward the unraveling of tumorigenic mechanisms induced by aberrant WNT signaling and SMARCA4 deficiency.
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Affiliation(s)
- Carolin Göbel
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg D-20251, Germany
- Research Institute Children's Cancer Center Hamburg, Hamburg D-20251, Germany
| | - Melanie Schoof
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg D-20251, Germany
- Research Institute Children's Cancer Center Hamburg, Hamburg D-20251, Germany
| | - Dörthe Holdhof
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg D-20251, Germany
- Research Institute Children's Cancer Center Hamburg, Hamburg D-20251, Germany
| | - Michael Spohn
- Research Institute Children's Cancer Center Hamburg, Hamburg D-20251, Germany
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg D-20251, Germany
| | - Ulrich Schüller
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg D-20251, Germany
- Research Institute Children's Cancer Center Hamburg, Hamburg D-20251, Germany
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20251, Germany
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11
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Kumar R, Rottner K, Rao GN. Requirement of Site-Specific Tyrosine Phosphorylation of Cortactin in Retinal Neovascularization and Vascular Leakage. Arterioscler Thromb Vasc Biol 2024; 44:366-390. [PMID: 38126170 PMCID: PMC10872470 DOI: 10.1161/atvbaha.123.320279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND Retinal neovascularization is a major cause of vision impairment. Therefore, the purpose of this study is to investigate the mechanisms by which hypoxia triggers the development of abnormal and leaky blood vessels. METHODS A variety of cellular and molecular approaches as well as tissue-specific knockout mice were used to investigate the role of Cttn (cortactin) in retinal neovascularization and vascular leakage. RESULTS We found that VEGFA (vascular endothelial growth factor A) stimulates Cttn phosphorylation at Y421, Y453, and Y470 residues in human retinal microvascular endothelial cells. In addition, we observed that while blockade of Cttn phosphorylation at Y470 inhibited VEGFA-induced human retinal microvascular endothelial cell angiogenic events, suppression of Y421 phosphorylation protected endothelial barrier integrity from disruption by VEGFA. In line with these observations, while blockade of Cttn phosphorylation at Y470 negated oxygen-induced retinopathy-induced retinal neovascularization, interference with Y421 phosphorylation prevented VEGFA/oxygen-induced retinopathy-induced vascular leakage. Mechanistically, while phosphorylation at Y470 was required for its interaction with Arp2/3 and CDC6 facilitating actin polymerization and DNA synthesis, respectively, Cttn phosphorylation at Y421 leads to its dissociation from VE-cadherin, resulting in adherens junction disruption. Furthermore, whereas Cttn phosphorylation at Y470 residue was dependent on Lyn, its phosphorylation at Y421 residue required Syk activation. Accordingly, lentivirus-mediated expression of shRNA targeting Lyn or Syk levels inhibited oxygen-induced retinopathy-induced retinal neovascularization and vascular leakage, respectively. CONCLUSIONS The above observations show for the first time that phosphorylation of Cttn is involved in a site-specific manner in the regulation of retinal neovascularization and vascular leakage. In view of these findings, Cttn could be a novel target for the development of therapeutics against vascular diseases such as retinal neovascularization and vascular leakage.
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Affiliation(s)
- Raj Kumar
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Klemens Rottner
- Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany
- Department of Cell Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany
| | - Gadiparthi N. Rao
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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12
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Yang Q, Zhuo Z, Qiu X, Luo R, Guo K, Wu H, Jiang R, Li J, Lian Q, Chen P, Sha W, Chen H. Adverse clinical outcomes and immunosuppressive microenvironment of RHO-GTPase activation pattern in hepatocellular carcinoma. J Transl Med 2024; 22:122. [PMID: 38297333 PMCID: PMC10832138 DOI: 10.1186/s12967-024-04926-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 01/23/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Emerging evidence suggests that Rho GTPases play a crucial role in tumorigenesis and metastasis, but their involvement in the tumor microenvironment (TME) and prognosis of hepatocellular carcinoma (HCC) is not well understood. METHODS We aim to develop a tumor prognosis prediction system called the Rho GTPases-related gene score (RGPRG score) using Rho GTPase signaling genes and further bioinformatic analyses. RESULTS Our work found that HCC patients with a high RGPRG score had significantly worse survival and increased immunosuppressive cell fractions compared to those with a low RGPRG score. Single-cell cohort analysis revealed an immune-active TME in patients with a low RGPRG score, with strengthened communication from T/NK cells to other cells through MIF signaling networks. Targeting these alterations in TME, the patients with high RGPRG score have worse immunotherapeutic outcomes and decreased survival time in the immunotherapy cohort. Moreover, the RGPRG score was found to be correlated with survival in 27 other cancers. In vitro experiments confirmed that knockdown of the key Rho GTPase-signaling biomarker SFN significantly inhibited HCC cell proliferation, invasion, and migration. CONCLUSIONS This study provides new insight into the TME features and clinical use of Rho GTPase gene pattern at the bulk-seq and single-cell level, which may contribute to guiding personalized treatment and improving clinical outcome in HCC.
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Affiliation(s)
- Qi Yang
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zewei Zhuo
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Xinqi Qiu
- Cancer Prevention Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Ruibang Luo
- Department of Computer Science, The University of Hong Kong, Hong Kong, 999077, SAR, China
| | - Kehang Guo
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China
- Department of Critical Care Medicine, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Huihuan Wu
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Rui Jiang
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Jingwei Li
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Qizhou Lian
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518118, Guangdong, China.
- Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, 999077, SAR, China.
| | - Pengfei Chen
- Department of Laboratory Medicine, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China.
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China.
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13
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Meng W, Xiao H, Zhao R, Chen J, Wang Y, Mei P, Li H, Liao Y. METTL3 drives NSCLC metastasis by enhancing CYP19A1 translation and oestrogen synthesis. Cell Biosci 2024; 14:10. [PMID: 38238831 PMCID: PMC10795463 DOI: 10.1186/s13578-024-01194-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 01/10/2024] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND METTL3 plays a significant role as a catalytic enzyme in mediating N6-methyladenosine (m6A) modification, and its importance in tumour progression has been extensively studied in recent years. However, the precise involvement of METTL3 in the regulation of translation in non-small cell lung cancer (NSCLC) remains unclear. RESULTS Here we discovered by clinical investigation that METTL3 expression is correlated with NSCLC metastasis. Ablation of METTL3 in NSCLC cells inhibits invasion and metastasis in vitro and in vivo. Subsequently, through translatomics data mining and experimental validation, we demonstrated that METTL3 enhances the translation of aromatase (CYP19A1), a key enzyme in oestrogen synthesis, thereby promoting oestrogen production and mediating the invasion and metastasis of NSCLC. Mechanistically, METTL3 interacts with translation initiation factors and binds to CYP19A1 mRNA, thus enhancing the translation efficiency of CYP19A1 in an m6A-dependent manner. Pharmacological inhibition of METTL3 enzymatic activity or translation initiation factor eIF4E abolishes CYP19A1 protein synthesis. CONCLUSIONS Our findings indicate the crucial role of METTL3-mediated translation regulation in NSCLC and reveal the significance of METTL3/eIF4E/CYP19A1 signaling as a promising therapeutic target for anti-metastatic strategies against NSCLC.
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Affiliation(s)
- Wangyang Meng
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Han Xiao
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
| | - Rong Zhao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jiaping Chen
- Department of Cardiothoracic Surgery, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, Yunnan, China
| | - Yangwei Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Peiyuan Mei
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hecheng Li
- Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Yongde Liao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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R P, Shanmugam G, Rakshit S, Sarkar K. Role of Wiskott Aldrich syndrome protein in haematological malignancies: genetics, molecular mechanisms and therapeutic strategies. Pathol Res Pract 2024; 253:155026. [PMID: 38118219 DOI: 10.1016/j.prp.2023.155026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/07/2023] [Accepted: 12/07/2023] [Indexed: 12/22/2023]
Abstract
As patients continue to suffer from lymphoproliferative and myeloproliferative diseases known as haematopoietic malignancies can affect the bone marrow, blood, lymph nodes, and lymphatic and non-lymphatic organs. Despite advances in the current treatment, there is still a significant challenge for physicians to improve the therapy of HMs. WASp is an important regulator of actin polymerization and the involvement of WASp in transcription is thought to be linked to the DNA damage response and repair. In some studies, severe immunodeficiency and lymphoid malignancy are caused by WASp mutations or the absence of WASp and these mutations in WAS can alter the function and/or expression of the intracellular protein. Loss-of-function and Gain-of-function mutations in WASp have an impact on cancer malignancies' incidence and onset. Recent studies suggest that depending on the clinical or experimental situation, WASPs and WAVEs can operate as a suppressor or enhancers for cancer malignancy. These dual functions of WASPs and WAVEs in cancer likely arose from their multifaceted role in cells that could be targeted for anticancer drug development. The significant role and their association of WASp in Chronic myeloid leukaemia, Juvenile myelomonocytic leukaemia and T-cell lymphoma is discussed. In this review, we described the structure and function of WASp and its family mechanism, analysing major regulatory effectors and summarising the clinical relevance and drugs that specifically target WASp in disease treatment in various hematopoietic malignancies by different approaches.
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Affiliation(s)
- Pradeep R
- Department of Biotechnology, SRM Institute of Science and Technology, Katangulathur, Tamil Nadu 603203, India
| | - Geetha Shanmugam
- Department of Biotechnology, SRM Institute of Science and Technology, Katangulathur, Tamil Nadu 603203, India
| | - Sudeshna Rakshit
- Department of Biotechnology, SRM Institute of Science and Technology, Katangulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Katangulathur, Tamil Nadu 603203, India.
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15
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Hu G, Huang N, Zhang J, Zhang D, Wang S, Zhang Y, Wang L, Du Y, Kuang S, Ma K, Zhu H, Xu N, Liu M. LKB1 loss promotes colorectal cancer cell metastasis through regulating TNIK expression and actin cytoskeleton remodeling. Mol Carcinog 2023; 62:1659-1672. [PMID: 37449799 DOI: 10.1002/mc.23606] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 05/19/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors. Approximately 5%-6% of CRC cases are associated with hereditary CRC syndromes, including the Peutz-Jeghers syndrome (PJS). Liver kinase B1 (LKB1), also known as STK11, is the major gene responsible for PJS. LKB1 heterozygotic deficiency is involved in intestinal polyps in mice, while the mechanism of LKB1 in CRC remains elusive. In this study, we generated LKB1 knockout (KO) CRC cell lines by using CRISPR-Cas9. LKB1 KO promoted CRC cell motility in vitro and tumor metastases in vivo. LKB1 attenuated expression of TRAF2 and NCK-interacting protein kinase (TNIK) as accessed by RNA-seq and western blots, and similar suppression was also detected in the tumor tissues of azoxymethane/dextran sodium sulfate-induced intestinal-specific LKB1-KO mice. LKB1 repressed TNIK expression through its kinase activity. Moreover, attenuating TNIK by shRNA inhibited cell migration and invasion of CRC cells. LKB1 loss-induced high metastatic potential of CRC cells was depended on TNIK upregulation. Furthermore, TNIK interacted with ARHGAP29 and further affected actin cytoskeleton remodeling. Taken together, LKB1 deficiency promoted CRC cell metastasis via TNIK upregulation and subsequently mediated cytoskeleton remodeling. These results suggest that LKB1-TNIK axis may play a crucial role in CRC progression.
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Affiliation(s)
- Guanghui Hu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Die Zhang
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuren Wang
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuanyuan Zhang
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Panjiayuan, Chaoyang District, Beijing, People's Republic of China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingxi Du
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuwen Kuang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kai Ma
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ningzhi Xu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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16
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Li Z, Zhu H, Liu H, Liu D, Liu J, Jiang J, Zhang Y, Qin Z, Xu Y, Peng Y, Liu B, Long Y. Evolocumab loaded Bio-Liposomes for efficient atherosclerosis therapy. J Nanobiotechnology 2023; 21:158. [PMID: 37208681 DOI: 10.1186/s12951-023-01904-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/19/2023] [Indexed: 05/21/2023] Open
Abstract
PCSK9, which is closely related to atherosclerosis, is significantly expressed in vascular smooth muscle cells (VSMCs). Moreover, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) mediated phenotypic transformation, abnormal proliferation, and migration of VSMCs play key roles in accelerating atherosclerosis. In this study, by utilizing the significant advantages of nano-materials, a biomimetic nanoliposome loading with Evolocumab (Evol), a PCSK9 inhibitor, was designed to alleviate atherosclerosis. In vitro results showed that (Lipo + M)@E NPs up-regulated the levels of α-SMA and Vimentin, while inhibiting the expression of OPN, which finally result in the inhibition of the phenotypic transition, excessive proliferation, and migration of VSMCs. In addition, the long circulation, excellent targeting, and accumulation performance of (Lipo + M)@E NPs significantly decreased the expression of PCSK9 in serum and VSMCs within the plaque of ApoE-/- mice.
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Affiliation(s)
- Zhenxian Li
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China
| | - Haimei Zhu
- Department of Pain, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, China
| | - Hao Liu
- Department of Rehabilitation, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Dayue Liu
- Department of Physiology and Pathophysiology, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China
| | - Jianhe Liu
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China
| | - Jiazheng Jiang
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China
| | - Yi Zhang
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China
| | - Zhang Qin
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China
| | - Yijia Xu
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China
| | - Yuan Peng
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China
| | - Bin Liu
- College of Biology, Hunan University, Changsha, 410082, China.
- Department of Physiology and Pathophysiology, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China.
| | - Yun Long
- Department of Cardiology, The First Hospital of Hunan University of Chinese Medicine, Branch of National Clinical Research Center for Chinese Medicine Cardiology, Changsha, 410007, China.
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17
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The actin bundling activity of ITPKA mainly accounts for its migration-promoting effect in lung cancer cells. Biosci Rep 2023; 43:232487. [PMID: 36688944 PMCID: PMC9912108 DOI: 10.1042/bsr20222150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/29/2022] [Accepted: 01/09/2023] [Indexed: 01/24/2023] Open
Abstract
Expression of Ins(1,4,5)P3-kinase-A (ITPKA), the neuronal isoform of Ins(1,4,5)P3-kinases, is up-regulated in many tumor types. In particular, in lung cancer cells this up-regulation is associated with bad prognosis and it has been shown that a high level of ITPKA increases migration and invasion of lung cancer cell lines. However, since ITPKA exhibits actin bundling and Ins(1,4,5)P3-kinase activity, it was not clear which of these activities account for ITPKA-promoted migration and invasion of cancer cells. To address this issue, we inhibited endogenous actin bundling activity of ITPKA in lung cancer H1299 cells by overexpressing the dominant negative mutant ITPKAL34P. Analysis of actin dynamics in filopodia as well as wound-healing migration revealed that ITPKAL34P inhibited both processes. Moreover, the formation of invasive protrusions into collagen I was strongly blocked in cells overexpressing ITPKAL34P. Furthermore, we found that ATP stimulation slightly but significantly (by 13%) increased migration of cells overexpressing ITPKA while under basal conditions up-regulation of ITPKA had no effect. In accordance with these results, overexpression of a catalytic inactive ITPKA mutant did not affect migration, and the Ins(1,4,5)P3-kinase-inhibitor GNF362 reversed the stimulating effect of ITPKA overexpression on migration. In summary, we demonstrate that under basal conditions the actin bundling activity controls ITPKA-facilitated migration and invasion and in presence of ATP the Ins(1,4,5)P3-kinase activity slightly enhances this effect.
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18
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Wei J, Meng G, Wu J, Wei Z, Zhang Q, Bao J, Zhang J. CAPZA1 is low expressed in non-small cell lung cancer and contributed to tumor cell proliferation and metastasis. Minerva Med 2023; 114:124-126. [PMID: 32914610 DOI: 10.23736/s0026-4806.20.06910-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Jinying Wei
- Department of Respiratory and Critical Care Medicine, the Second Hospital of Jilin University, Changchun, China.,Department of General Practice, the First Hospital of Jilin University, Changchun, China
| | - Guangping Meng
- Department of Respiratory and Critical Care Medicine, the Second Hospital of Jilin University, Changchun, China
| | - Jing Wu
- Department of General Practice, the First Hospital of Jilin University, Changchun, China
| | - Zhouxia Wei
- Department of General Practice, the First Hospital of Jilin University, Changchun, China
| | - Qiang Zhang
- Department of General Practice, the First Hospital of Jilin University, Changchun, China
| | - Jin Bao
- Department of Health Examination Center, the First Hospital of Jilin University, Changchun, China
| | - Jie Zhang
- Department of Respiratory and Critical Care Medicine, the Second Hospital of Jilin University, Changchun, China -
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19
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Sun T, Tong W, Pu J, Yu Z, Kang Z. SH3BP1 Regulates Melanoma Progression Through Race1/Wace2 Signaling Pathway. Clin Med Insights Oncol 2023; 17:11795549231168075. [PMID: 37114076 PMCID: PMC10126683 DOI: 10.1177/11795549231168075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/15/2023] [Indexed: 04/29/2023] Open
Abstract
Background SH3-domain binding protein-1 (SH3BP1), which specifically inactivates Rac1 and its target protein Wave2, has been shown to be an important regulator of cancer metastasis. However, the effects of SH3BP1 in melanoma progression remain unclear. The current study aimed to explore the function of SH3BP1 in melanoma and its possible molecular mechanism. Methods TCGA database was used to analyze the expression of SH3BP1 in melanoma. Then, reverse transcription-quantitative polymerase chain reaction was performed to detect the expression of SH3BP1 in melanoma tissues and cells. Next, genes related to SH3BP1 were analyzed by LinkedOmics database, and protein interactions were analyzed by STRING database. These genes were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In addition, the signaling pathway of SH3BP1 action was screened by bioinformatics analysis. Finally, the function of SH3BP1 and its mediated signaling pathway in melanoma progression were investigated in vitro and in vivo. Results SH3BP1 was significantly upregulated in melanoma tissues and cells. The pathways regulated by SH3BP1 are closely related to the occurrence and development of tumors. And we found that overexpression of SH3BP1 promoted the proliferation, migration, and invasion of melanoma cells by increasing Rac1 activity and Wave2 protein levels in vitro. Similarly, overexpression of SH3BP1 facilitated melanoma progression by upregulating Wave2 protein expression in vivo. Conclusion In summary, this study revealed for the first time that SH3BP1 promoted melanoma progression through Rac1/Wave2 signaling pathway, providing a new therapeutic target for melanoma.
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Affiliation(s)
- Ting Sun
- Department of Dermatology, Middle
Military Command General Hospital of PLA, Wuhan, China
| | - Wenxian Tong
- Department of Oncology, The Fifth
Hospital of Wuhan, Wuhan, China
| | - Jie Pu
- Department of Neurology, Renmin
Hospital of Wuhan University, Wuhan, China
| | - Zhiguo Yu
- Department of Emergency, Central
Theater General Hospital, Wuhan, China
| | - Zhengchun Kang
- Department of Colorectal Surgery,
Changhai Hospital, Naval Medical University, Shanghai, China
- Zhengchun Kang, Department of Colorectal
Surgery, Changhai Hospital, Naval Medical University, 168 Changhai Road, Yangpu
District, Shanghai 200433, China.
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20
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Ji X, Tian X, Feng S, Zhang L, Wang J, Guo R, Zhu Y, Yu X, Zhang Y, Du H, Zablotskii V, Zhang X. Intermittent F-actin Perturbations by Magnetic Fields Inhibit Breast Cancer Metastasis. RESEARCH (WASHINGTON, D.C.) 2023; 6:0080. [PMID: 36939445 PMCID: PMC10017101 DOI: 10.34133/research.0080] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/31/2023] [Indexed: 02/04/2023]
Abstract
F-actin (filamentous actin) has been shown to be sensitive to mechanical stimuli and play critical roles in cell attachment, migration, and cancer metastasis, but there are very limited ways to perturb F-actin dynamics with low cell toxicity. Magnetic field is a noninvasive and reversible physical tool that can easily penetrate cells and human bodies. Here, we show that 0.1/0.4-T 4.2-Hz moderate-intensity low-frequency rotating magnetic field-induced electric field could directly decrease F-actin formation in vitro and in vivo, which results in decreased breast cancer cell migration, invasion, and attachment. Moreover, low-frequency rotating magnetic fields generated significantly different effects on F-actin in breast cancer vs. noncancerous cells, including F-actin number and their recovery after magnetic field retrieval. Using an intermittent treatment modality, low-frequency rotating magnetic fields could significantly reduce mouse breast cancer metastasis, prolong mouse survival by 31.5 to 46.0% (P < 0.0001), and improve their overall physical condition. Therefore, our work demonstrates that low-frequency rotating magnetic fields not only can be used as a research tool to perturb F-actin but also can inhibit breast cancer metastasis through F-actin modulation while having minimum effects on normal cells, which reveals their potential to be developed as temporal-controlled, noninvasive, and high-penetration physical treatments for metastatic cancer.
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Affiliation(s)
- Xinmiao Ji
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
| | - Xiaofei Tian
- Institutes of Physical Science and Information Technology,
Anhui University, Hefei, Anhui, 230601, P. R. China
| | - Shuang Feng
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
| | - Lei Zhang
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
| | - Junjun Wang
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
| | - Ruowen Guo
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
- Science Island Branch of Graduate School,
University of Science and Technology of China, Hefei, Anhui 230031, P.R China
| | - Yiming Zhu
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
- Science Island Branch of Graduate School,
University of Science and Technology of China, Hefei, Anhui 230031, P.R China
| | - Xin Yu
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
- Science Island Branch of Graduate School,
University of Science and Technology of China, Hefei, Anhui 230031, P.R China
| | - Yongsen Zhang
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
| | - Haifeng Du
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
| | - Vitalii Zablotskii
- Institute of Physics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Xin Zhang
- High Magnetic Field Laboratory of CAS (CHMFL), CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,
HFIPS, Hefei, Anhui 230031, P.R China
- Institutes of Physical Science and Information Technology,
Anhui University, Hefei, Anhui, 230601, P. R. China
- Science Island Branch of Graduate School,
University of Science and Technology of China, Hefei, Anhui 230031, P.R China
- International Magnetobiology Frontier Research Center, Science Island, Hefei 230031, P.R. China
- Address correspondence to:
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21
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Na S, Cui H, Guo Z, Liang X, Sakran KA, Guo X, Li X, Xie L, Zhu Y, Qi H, Tu J. Overexpression of Mena is associated with tumor progression and poor prognosis in oral squamous cell carcinoma via EMT. Front Oncol 2022; 12:1052375. [PMID: 36620546 PMCID: PMC9822539 DOI: 10.3389/fonc.2022.1052375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Background Mena, a cytoskeletal regulatory protein, is involved in actin-based regulation of cell motility and adhesion, and contributes to tumor invasion and metastasis. However, the role of Mena in oral squamous cell carcinoma remains unclear. This is the first research focusing on the prognostic value of Mena in OSCC. In this study, we aimed to investigate the correlation between Mena expression and clinicopathological significance, as well as prognostic value in OSCC. Methods Mena gene expression profiles of OSCC and normal tissues were collected from Oncomine, TCGA, and GEO databases. Biological function was analyzed through GO, KEGG and GSEA enrichment. Further, the expression level of Mena and tumor-related markers in 151 OSCC specimens was examined by IHC staining based on tissue microarray. Kaplan-Meier analysis was used to assess the prognostic performance of Mena in OSCC. Result Mena was generally upregulation in various malignancies, especially OSCC. The functional analyses indicated that Mena was involved in the assembly and regulation of actin, cell movement, and EMT. IHC staining revealed that high expression of Mena in OSCC was correlated with Lymphatic metastasis, TNM stage, E-cadherin, Vimentin, and MMP-2, but insignificantly Ki67. Kaplan-Meier analysis demonstrated that elevated expression of Mena was significantly associated with poor overall survival and disease-free survival of OSCC patients. Conclusion Mena could be a novel biomarker for predicting the prognosis of OSCC patients, which supports a theoretical basis for developing molecular target therapy.
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Affiliation(s)
- Sijia Na
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Hao Cui
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Zhichen Guo
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xiang Liang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Karim Ahmed Sakran
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China,Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xiaomei Guo
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Pathology, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xingqiang Li
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Linyang Xie
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yifei Zhu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Hong Qi
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Pathology, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,*Correspondence: Hong Qi, ; Junbo Tu,
| | - Junbo Tu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,Department of Oral and Maxillofacial Surgery, College of Stomatology, Xi’an Jiaotong University, Xi’an, Shaanxi, China,*Correspondence: Hong Qi, ; Junbo Tu,
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Sun X, Zhou L, Wang X, Li Y, Liu X, Chen Y, Zhong Z, Chen J. FYCO1 regulates migration, invasion, and invadopodia formation in HeLa cells through CDC42/N-WASP/Arp2/3 signaling pathway. Biochem Cell Biol 2022; 100:458-472. [PMID: 36342046 DOI: 10.1139/bcb-2021-0575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
FYCO1, an autophagy adaptor, plays an essential role in the trafficking toward the plus-end of microtubules and the fusion of autophagosomes. Autophagic dysfunction is involved in numerous disease states, including cancers. Previous studies have implicated FYCO1 as one of the critical genes involved in the adenoma to carcinoma transition, but the biological function and mechanism of FYCO1 in carcinogenesis remain unclear. This study aims to elucidate the role and mechanism of up- and downregulation of FYCO1 in mediating tumor effects in HeLa cells. Functionally, FYCO1 promotes cellular migration, invasion, epithelial-mesenchymal transition, invadopodia formation, and matrix degradation, which are detected through wound healing, transwell, immunofluorescence, and Western blot approaches. Interestingly, the data show that although FYCO1 does not affect HeLa cell proliferation, cell cycle distribution, nor vessels' formation, FYCO1 can block the apoptotic function. FYCO1 inhibits cleavage of PARP, caspase3, and caspase9 and increases Bcl-2/Bax ratio. Then, we used CK666, an Arp2/3 specific inhibitor, to confirm that FYCO1 may promote the migration and invasion of HeLa cells through the CDC42/N-WASP/Arp2/3 signaling pathway. Taken together, these results provide a new insight that FYCO1, an autophagy adaptor, may also be a new regulator of tumor metastasis.
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Affiliation(s)
- Xuejiao Sun
- Translational Research Institute of Brain and Brain-like Intelligence, People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China.,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Linlin Zhou
- Translational Research Institute of Brain and Brain-like Intelligence, People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China.,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Xinyao Wang
- Translational Research Institute of Brain and Brain-like Intelligence, People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China.,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Yuying Li
- Translational Research Institute of Brain and Brain-like Intelligence, People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China.,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Xiangyuan Liu
- Translational Research Institute of Brain and Brain-like Intelligence, People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China.,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Yu Chen
- Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Zilin Zhong
- Translational Research Institute of Brain and Brain-like Intelligence, People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China.,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Jianjun Chen
- Translational Research Institute of Brain and Brain-like Intelligence, People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Pediatrics, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.,Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China.,Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
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Jang HJ, Yoon YJ, Choi J, Lee YJ, Lee S, Cho W, Byun WG, Park SB, Han DC, Kwon BM. S-Benproperine, an Active Stereoisomer of Benproperine, Suppresses Cancer Migration and Tumor Metastasis by Targeting ARPC2. Pharmaceuticals (Basel) 2022; 15:ph15121462. [PMID: 36558913 PMCID: PMC9785746 DOI: 10.3390/ph15121462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Metastasis, in which cancer cells migrate to other tissues and form new tumors, is a major cause of both cancer death and treatment failure. In a previous study, benproperine (Benp) was identified as a cancer cell migration inhibitor and an inhibitor of actin-related protein 2/3 complex subunit 2 (ARPC2). However, Benp is a racemic mixture, and which stereoisomer is the active isomer remains unclear. In this study, we found that S-Benp is an active isomer and inhibits the migration and invasion of cancer cells much more strongly than R-Benp, with no effect on normal cells. The metastasis inhibitory effect of S-Benp was also verified in an animal model. Validating that inhibitors bind to their targets in cells and tissues has been a very challenging task in drug discovery. The direct interactions between ARPC2 and S-Benp were verified by surface plasmon resonance analysis (SPR), a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). In the mutant study with ARPC2F225A cells, S-Benp did not bind to ARPC2F225A according to CETSA and DARTS. Furthermore, we validated that S-Benp colocalized with ARPC2 in cancer cells and directly bound to ARPC2 in tumor tissues using Cy3-conjugated S-Benp according to CETSA. Finally, actin polymerization assays and immunocytochemistry showed that S-Benp suppressed actin remodeling such as lamellipodium formation. Taken together, our data suggest that S-Benp is an active stereoisomer of Benp and a potential metastasis inhibitor via ARPC2 binding.
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Affiliation(s)
- Hyun-Jin Jang
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea
| | - Yae Jin Yoon
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea
| | - Jiyeon Choi
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea
| | - Yu-Jin Lee
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea
| | - Sangku Lee
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea
| | - Wansang Cho
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
| | - Wan Gi Byun
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
| | - Seung Bum Park
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
| | - Dong Cho Han
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea
- KRIBB School of Bioscience, University of Science and Technology in Korea, 217 Gajeongro, Daejeon 34113, Republic of Korea
- Correspondence: (D.C.H.); (B.-M.K.)
| | - Byoung-Mog Kwon
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Republic of Korea
- Central Research Institute, VS Pharm Tech Co., Ltd., Daejeon 35209, Republic of Korea
- Correspondence: (D.C.H.); (B.-M.K.)
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Xue Y, Li M, Hu J, Song Y, Guo W, Miao C, Ge D, Hou Y, Wang X, Huang X, Liu T, Zhang X, Huang Q. Ca v2.2-NFAT2-USP43 axis promotes invadopodia formation and breast cancer metastasis through cortactin stabilization. Cell Death Dis 2022; 13:812. [PMID: 36137995 PMCID: PMC9500045 DOI: 10.1038/s41419-022-05174-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 08/03/2022] [Accepted: 08/09/2022] [Indexed: 01/23/2023]
Abstract
Distant metastasis is the main cause of mortality in breast cancer patients. Using the breast cancer genomic data from The Cancer Genome Atlas (TCGA), we identified brain specific Cav2.2 as a critical regulator of metastasis. Cav2.2 expression is significantly upregulated in breast cancer and its higher expression is inversely correlated with survival suggesting a previously unappreciated role of Cav2.2 in breast cancer. Cav2.2 is required for breast cancer migration, invasion, and metastasis. Interestingly, Cav2.2 promotes invadopodia formation and extracellular matrix (ECM) degradation through the stabilization of invadopodia component cortactin in a proteosome-dependent manner. Moreover, deubiquitinating enzyme USP43 mediated the functions of Cav2.2 in cortactin stabilization, invadopodia formation, ECM degradation, and metastasis. Interestingly, Cav2.2 upregulates USP43 expression through NFAT2 dephosphorylation and nuclear localization. Our study uncovered a novel pathway that regulates cortactin expression and invadopodia formation in breast cancer metastasis.
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Affiliation(s)
- Ying Xue
- grid.8547.e0000 0001 0125 2443Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China ,grid.8547.e0000 0001 0125 2443Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Min Li
- grid.8547.e0000 0001 0125 2443Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China ,grid.8547.e0000 0001 0125 2443Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Jie Hu
- grid.8547.e0000 0001 0125 2443Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Yuanlin Song
- grid.8547.e0000 0001 0125 2443Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Wei Guo
- grid.8547.e0000 0001 0125 2443Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Changhong Miao
- grid.8547.e0000 0001 0125 2443Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China ,grid.8547.e0000 0001 0125 2443Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Di Ge
- grid.8547.e0000 0001 0125 2443Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Yingyong Hou
- grid.8547.e0000 0001 0125 2443Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Xuefei Wang
- grid.8547.e0000 0001 0125 2443Department of General Surgery/Gastric Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Xingxu Huang
- grid.440637.20000 0004 4657 8879School of Life Science and Technology, ShanghaiTech University, Shanghai, PR China
| | - Tianshu Liu
- grid.8547.e0000 0001 0125 2443Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China ,grid.8547.e0000 0001 0125 2443Department of Medicial Oncology, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Xiaoping Zhang
- grid.24516.340000000123704535The Institute of Intervention Vessel, Tongji University School of Medicine, Shanghai, PR China
| | - Qihong Huang
- grid.8547.e0000 0001 0125 2443Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China ,grid.8547.e0000 0001 0125 2443Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, PR China ,grid.413087.90000 0004 1755 3939Shanghai Respiratory Research Institute, Shanghai, PR China
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Voxtalisib and Low Intensity Pulsed Ultrasound Combinatorial Effect On Glioblastoma Multiforme Cancer Stem Cells Via PI3K/AKT/mTOR. Pathol Res Pract 2022; 239:154145. [DOI: 10.1016/j.prp.2022.154145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/15/2022] [Accepted: 09/26/2022] [Indexed: 11/22/2022]
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Pudelko K, Wieland A, Hennecke M, Räschle M, Bastians H. Increased Microtubule Growth Triggered by Microvesicle-mediated Paracrine Signaling is Required for Melanoma Cancer Cell Invasion. CANCER RESEARCH COMMUNICATIONS 2022; 2:366-379. [PMID: 36875714 PMCID: PMC9981201 DOI: 10.1158/2767-9764.crc-22-0010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/25/2022] [Accepted: 05/03/2022] [Indexed: 11/16/2022]
Abstract
The acquisition of cell invasiveness is the key transition from benign melanocyte hyperplasia to aggressive melanoma. Recent work has provided an intriguing new link between the presence of supernumerary centrosomes and increased cell invasion. Moreover, supernumerary centrosomes were shown to drive non-cell-autonomous invasion of cancer cells. Although centrosomes are the principal microtubule organizing centers, the role of dynamic microtubules for non-cell-autonomous invasion remains unexplored, in particular, in melanoma. We investigated the role of supernumerary centrosomes and dynamic microtubules in melanoma cell invasion and found that highly invasive melanoma cells are characterized by the presence of supernumerary centrosomes and by increased microtubule growth rates, both of which are functionally interlinked. We demonstrate that enhanced microtubule growth is required for increased three-dimensional melanoma cell invasion. Moreover, we show that the activity to enhance microtubule growth can be transferred onto adjacent noninvasive cells through microvesicles involving HER2. Hence, our study suggests that suppressing microtubule growth, either directly using anti-microtubule drugs or through HER2 inhibitors might be therapeutically beneficial to inhibit cell invasiveness and thus, metastasis of malignant melanoma. Significance This study shows that increased microtubule growth is required for melanoma cell invasion and can be transferred onto adjacent cells in a non-cell-autonomous manner through microvesicles involving HER2.
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Affiliation(s)
- Karoline Pudelko
- Institute of Molecular Oncology, Section for Cellular Oncology, Georg-August University Göttingen, University Medical Center Göttingen (UMG) and Göttingen Center for Molecular Biosciences (GZMB), Göttingen, Germany
| | - Angela Wieland
- Department of Molecular Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany
| | - Magdalena Hennecke
- Institute of Molecular Oncology, Section for Cellular Oncology, Georg-August University Göttingen, University Medical Center Göttingen (UMG) and Göttingen Center for Molecular Biosciences (GZMB), Göttingen, Germany
| | - Markus Räschle
- Department of Molecular Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany
| | - Holger Bastians
- Institute of Molecular Oncology, Section for Cellular Oncology, Georg-August University Göttingen, University Medical Center Göttingen (UMG) and Göttingen Center for Molecular Biosciences (GZMB), Göttingen, Germany
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27
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Li L, Gao S, Wang L, Bu T, Chu J, Lv L, Tahir A, Mao B, Li H, Li X, Wang Y, Wu X, Ge R, Cheng CY. PCP Protein Inversin Regulates Testis Function Through Changes in Cytoskeletal Organization of Actin and Microtubules. Endocrinology 2022; 163:6519617. [PMID: 35106541 PMCID: PMC8870424 DOI: 10.1210/endocr/bqac009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Indexed: 02/03/2023]
Abstract
Inversin is an integrated component of the Frizzled (Fzd)/Dishevelled (Dvl)/Diversin planar cell polarity (PCP) complex that is known to work in concert with the Van Gogh-like protein (eg, Vangl2)/Prickle PCP complex to support tissue and organ development including the brain, kidney, pancreas, and others. These PCP protein complexes are also recently shown to confer developing haploid spermatid PCP to support spermatogenesis in adult rat testes. However, with the exception of Dvl3 and Vangl2, other PCP proteins have not been investigated in the testis. Herein, we used the technique of RNA interference (RNAi) to examine the role of inversin (Invs) in Sertoli cell (SC) and testis function by corresponding studies in vitro and in vivo. When inversin was silenced by RNAi using specific small interfering RNA duplexes by transfecting primary cultures of SCs in vitro or testes in vivo, it was shown that inversin knockdown (KD) perturbed the SC tight junction-barrier function in vitro and in vivo using corresponding physiological and integrity assays. More important, inversin exerted its regulatory effects through changes in the organization of the actin and microtubule cytoskeletons, including reducing the ability of their polymerization. These changes, in turn, induced defects in spermatogenesis by loss of spermatid polarity, disruptive distribution of blood-testis barrier-associated proteins at the SC-cell interface, appearance of multinucleated round spermatids, and defects in the release of sperm at spermiation.
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Affiliation(s)
- Linxi Li
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
- Correspondence: Linxi Li, PhD, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
| | - Sheng Gao
- Institute of Reproductive Medicine, Nantong University School of Medicine, Nantong, Jiangsu 226001, China
| | - Lingling Wang
- Institute of Reproductive Medicine, Nantong University School of Medicine, Nantong, Jiangsu 226001, China
| | - Tiao Bu
- Institute of Reproductive Medicine, Nantong University School of Medicine, Nantong, Jiangsu 226001, China
| | - Jinjin Chu
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Lixiu Lv
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Anam Tahir
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Baiping Mao
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Huitao Li
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Xiaoheng Li
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Yiyan Wang
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Xiaolong Wu
- Institute of Reproductive Medicine, Nantong University School of Medicine, Nantong, Jiangsu 226001, China
| | - Renshan Ge
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - C Yan Cheng
- The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
- Institute of Reproductive Medicine, Nantong University School of Medicine, Nantong, Jiangsu 226001, China
- Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China
- Correspondence: C. Yan Cheng, PhD, Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China. ;
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28
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Filopodia rotate and coil by actively generating twist in their actin shaft. Nat Commun 2022; 13:1636. [PMID: 35347113 PMCID: PMC8960877 DOI: 10.1038/s41467-022-28961-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 02/10/2022] [Indexed: 12/19/2022] Open
Abstract
Filopodia are actin-rich structures, present on the surface of eukaryotic cells. These structures play a pivotal role by allowing cells to explore their environment, generate mechanical forces or perform chemical signaling. Their complex dynamics includes buckling, pulling, length and shape changes. We show that filopodia additionally explore their 3D extracellular space by combining growth and shrinking with axial twisting and buckling. Importantly, the actin core inside filopodia performs a twisting or spinning motion which is observed for a range of cell types spanning from earliest development to highly differentiated tissue cells. Non-equilibrium physical modeling of actin and myosin confirm that twist is an emergent phenomenon of active filaments confined in a narrow channel which is supported by measured traction forces and helical buckles that can be ascribed to accumulation of sufficient twist. These results lead us to conclude that activity induced twisting of the actin shaft is a general mechanism underlying fundamental functions of filopodia. The authors show how tubular surface structures in all cell types, have the ability to twist and perform rotary sweeping motion to explore the extracellular environment. This has implications for migration, sensing and cell communication.
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Keum S, Yang SJ, Park E, Kang T, Choi JH, Jeong J, Hwang YE, Kim JW, Park D, Rhee S. Beta-Pix-dynamin 2 complex promotes colorectal cancer progression by facilitating membrane dynamics. Cell Oncol (Dordr) 2021; 44:1287-1305. [PMID: 34582006 PMCID: PMC8648671 DOI: 10.1007/s13402-021-00637-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 09/14/2021] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Spatiotemporal regulation of cell membrane dynamics is a major process that promotes cancer cell invasion by acting as a driving force for cell migration. Beta-Pix (βPix), a guanine nucleotide exchange factor for Rac1, has been reported to be involved in actin-mediated cellular processes, such as cell migration, by interacting with various proteins. As yet, however, the molecular mechanisms underlying βPix-mediated cancer cell invasion remain unclear. METHODS The clinical significance of βPix was analyzed in patients with colorectal cancer (CRC) using public clinical databases. Pull-down and immunoprecipitation assays were employed to identify novel binding partners for βPix. Additionally, various cell biological assays including immunocytochemistry and time-lapse video microscopy were performed to assess the effects of βPix on CRC progression. A βPix-SH3 antibody delivery system was used to determine the effects of the βPix-Dyn2 complex in CRC cells. RESULTS We found that the Src homology 3 (SH3) domain of βPix interacts with the proline-rich domain of Dynamin 2 (Dyn2), a large GTPase. The βPix-Dyn2 interaction promoted lamellipodia formation, along with plasma membrane localization of membrane-type 1 matrix metalloproteinase (MT1-MMP). Furthermore, we found that Src kinase-mediated phosphorylation of the tyrosine residue at position 442 of βPix enhanced βPix-Dyn2 complex formation. Disruption of the βPix-Dyn2 complex by βPix-SH3 antibodies targeting intracellular βPix inhibited CRC cell invasion. CONCLUSIONS Our data indicate that spatiotemporal regulation of the Src-βPix-Dyn2 axis is crucial for CRC cell invasion by promoting membrane dynamics and MT1-MMP recruitment into the leading edge. The development of inhibitors that disrupt the βPix-Dyn2 complex may be a useful therapeutic strategy for CRC.
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Affiliation(s)
- Seula Keum
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Soo Jung Yang
- Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, 98101, USA
| | - Esther Park
- School of Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - TaeIn Kang
- School of Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jee-Hye Choi
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Jangho Jeong
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Ye Eun Hwang
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Jung-Woong Kim
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Dongeun Park
- School of Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Sangmyung Rhee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
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Wang B, Zheng B, Cao L, Liao K, Huang D, Zhang Y, Jiang Y, Zheng S. T-lymphoma invasion and metastasis 1 promotes invadopodia formation and is regulated by the PI3K/Akt signaling pathway in hepatocellular carcinoma. Exp Cell Res 2021; 407:112806. [PMID: 34487727 DOI: 10.1016/j.yexcr.2021.112806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 08/22/2021] [Accepted: 08/27/2021] [Indexed: 10/25/2022]
Abstract
At present, there are still many poorly understood aspects of the mechanisms underlying hepatocellular carcinoma (HCC) invasion and metastasis. Invadopodia are important structures for cancer cell invasion and metastasis. We determined that high T-lymphoma invasion and metastasis 1 (Tiam1) expression is associated with HCC invasion and metastasis and poor patient prognosis after surgery. Gain- and loss-of-function studies confirmed that Tiam1 promotes invadopodia formation in HCC by activating Rac1. A series of biochemical experiments confirmed that this effect is regulated by the PI3K/Akt signaling pathway. We also confirmed that PIP2 facilitates this effect. In summary, these findings reveal that Tiam1 plays an important role in invadopodia formation in HCC.
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Affiliation(s)
- Baolin Wang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Department of Surgery, The 63650th Troop Hospital of the Chinese People's Liberation Army, Urumqi, Xinjinag, 841700, China
| | - Bowen Zheng
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Li Cao
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Kexi Liao
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Deng Huang
- Department of Hepatobiliary, General Hospital of Tibet Military Command Area, Lhasa, Tibet, 850000, China
| | - Yujun Zhang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yan Jiang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Shuguo Zheng
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies. Nat Commun 2021; 12:5581. [PMID: 34552085 PMCID: PMC8458504 DOI: 10.1038/s41467-021-25842-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 09/03/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott–Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner. Cancer cells proliferate and invade via cytoskeletal proteins such as WASp, exclusively expressed in hematopoietic cells. Here the authors show a specific small molecule compound inhibiting cancer cell activity by WASp degradation and demonstrating its therapeutic potential in vitro and in vivo.
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32
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Bergman E, Goldbart R, Traitel T, Amar‐Lewis E, Zorea J, Yegodayev K, Alon I, Rankovic S, Krieger Y, Rousso I, Elkabets M, Kost J. Cell stiffness predicts cancer cell sensitivity to ultrasound as a selective superficial cancer therapy. Bioeng Transl Med 2021; 6:e10226. [PMID: 34589601 PMCID: PMC8459597 DOI: 10.1002/btm2.10226] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 04/25/2021] [Accepted: 04/27/2021] [Indexed: 01/26/2023] Open
Abstract
We hypothesize that the biomechanical properties of cells can predict their viability, with Young's modulus representing the former and cell sensitivity to ultrasound representing the latter. Using atomic force microscopy, we show that the Young's modulus stiffness measure is significantly lower for superficial cancer cells (squamous cell carcinomas and melanoma) compared with noncancerous keratinocyte cells. In vitro findings reveal a significant difference between cancerous and noncancerous cell viability at the four ultrasound energy levels evaluated, with different cell lines exhibiting different sensitivities to the same ultrasound intensity. Young's modulus correlates with cell viability (R 2 = 0.93), indicating that this single biomechanical property can predict cell sensitivity to ultrasound treatment. In mice, repeated ultrasound treatment inhibits tumor growth without damaging healthy skin tissue. Histopathological tumor analysis indicates ultrasound-induced focal necrosis at the treatment site. Our findings provide a strong rationale for developing ultrasound as a noninvasive selective treatment for superficial cancers.
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Affiliation(s)
- Eden Bergman
- Department of Chemical EngineeringBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Riki Goldbart
- Department of Chemical EngineeringBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Tamar Traitel
- Department of Chemical EngineeringBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Eliz Amar‐Lewis
- Department of Chemical EngineeringBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Jonathan Zorea
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health SciencesBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Ksenia Yegodayev
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health SciencesBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Irit Alon
- Institute of PathologyBarzilai University Medical CenterAshkelonIsrael
- Department of Pathology, School of Health SciencesBen‐Gurion University of the NegevBeer‐ShebaIsrael
| | - Sanela Rankovic
- Department of Physiology and Cell BiologyBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Yuval Krieger
- Department of Plastic Surgery and Burn Unit, Faculty of Health SciencesSoroka University Medical Center, Ben‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Itay Rousso
- Department of Physiology and Cell BiologyBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health SciencesBen‐Gurion University of the NegevBeer‐ShevaIsrael
| | - Joseph Kost
- Department of Chemical EngineeringBen‐Gurion University of the NegevBeer‐ShevaIsrael
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Chi TH, Hsieh BY, Liang PS, Han TH, Hsieh M. Expression and Functional Study of Single Mutations of Carbonic Anhydrase 8 in Neuronal Cells. Cell Mol Neurobiol 2021; 41:1355-1371. [PMID: 32583043 PMCID: PMC11448582 DOI: 10.1007/s10571-020-00907-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/18/2020] [Indexed: 11/27/2022]
Abstract
Carbonic anhydrase 8 (CA8), an isozyme of α-carbonic anhydrases, lacks the ability to catalyze the reversible hydration of CO2 to bicarbonate and proton. Previous studies have shown that single point mutations of CA8, CA8-S100P, and CA8-G162R, are associated with novel syndromes including congenital ataxia and mild cognitive impairment. Our previous results demonstrated that overexpression of wild type (WT) CA8 promoted cell proliferation, neurite outgrowth, anti-apoptosis, invasion and migration abilities in neuronal cells. In this study, we examined the expressions and functions of CA8-S100P and CA8-G162R in neuroblastoma cells lines, compared with those of WT CA8. Our results show that the protein expressions of mutant CA8-S100P and CA8-G162R were significantly decreased in Neuro-2a and SK-N-SH cells. Interestingly, CA8-S100P demonstrated a significant increase in cell proliferation in both Neuro-2a and SK-N-SH cells. However, both CA8 mutations showed significantly decreased effects on cell protection and migration in SK-N-SH cells. Surprisingly, a significant increase of invasive ability was observed in SK-N-SH cells with overexpression of CA8-S100P as compared with those with overexpression of WT CA8 under retinoic acid (RA) treatment. In addition, we found that Neuro-2a cells with overexpression of CA8-S100P and CA8-G162R showed significantly increased neurite outgrowth. Taken together, our data suggest that the expressions of CA8-S100P and CA8-G162R in neuronal cells alter cell morphology, proliferation, mobility and viability; indicating that the homozygous point mutations of CA8 lead to not only the loss of WT CA8 function, but also the gain of novel functions leading to neuromuscular dysfunction.
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Affiliation(s)
- Tang-Hao Chi
- Department of Life Science, Tunghai University, No.1727, Sec. 4, Taiwan Boulevard, Taichung, 407, Taiwan, ROC
| | - Benjamin Y Hsieh
- Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Pei-Shin Liang
- Department of Life Science, Tunghai University, No.1727, Sec. 4, Taiwan Boulevard, Taichung, 407, Taiwan, ROC
| | - Tien-Heng Han
- Department of Life Science, Tunghai University, No.1727, Sec. 4, Taiwan Boulevard, Taichung, 407, Taiwan, ROC
| | - Mingli Hsieh
- Department of Life Science, Tunghai University, No.1727, Sec. 4, Taiwan Boulevard, Taichung, 407, Taiwan, ROC.
- Life Science Research Center, Tunghai University, Taichung, Taiwan, ROC.
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From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis. Cancers (Basel) 2021; 13:cancers13092024. [PMID: 33922182 PMCID: PMC8122743 DOI: 10.3390/cancers13092024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/09/2021] [Accepted: 04/20/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Despite the recent advances in human malignancy therapy, metastasis and chemoresistance remain the principal causes of cancer-derived deaths. Given the fatal forms of cutaneous metastatic melanoma, we herein employed primary (WM115) and metastatic (WM266-4) melanoma cells, both obtained from the same patient, to identify novel biomarkers and therapeutic agents. Through state-of-the-art technologies including deep proteome landscaping, immunofluorescence phenotyping, and drug toxicity screening, we were able to describe new molecular programs, oncogenic drivers, and drug regimens, controlling the invasion-metastasis cascade during BRAFV600D-dependent melanomagenesis. It proved that proteomic navigation could foster the development of systemic biomarkering and targeted drugging for successful treatment of advanced disease. Abstract Melanoma is classified among the most notoriously aggressive human cancers. Despite the recent progress, due to its propensity for metastasis and resistance to therapy, novel biomarkers and oncogenic molecular drivers need to be promptly identified for metastatic melanoma. Hence, by employing nano liquid chromatography-tandem mass spectrometry deep proteomics technology, advanced bioinformatics algorithms, immunofluorescence, western blotting, wound healing protocols, molecular modeling programs, and MTT assays, we comparatively examined the respective proteomic contents of WM115 primary (n = 3955 proteins) and WM266-4 metastatic (n = 6681 proteins) melanoma cells. It proved that WM115 and WM266-4 cells have engaged hybrid epithelial-to-mesenchymal transition/mesenchymal-to-epithelial transition states, with TGF-β controlling their motility in vitro. They are characterized by different signatures of SOX-dependent neural crest-like stemness and distinct architectures of the cytoskeleton network. Multiple signaling pathways have already been activated from the primary melanoma stage, whereas HIF1α, the major hypoxia-inducible factor, can be exclusively observed in metastatic melanoma cells. Invasion-metastasis cascade-specific sub-routines of activated Caspase-3-triggered apoptosis and LC3B-II-dependent constitutive autophagy were also unveiled. Importantly, WM115 and WM266-4 cells exhibited diverse drug response profiles, with epirubicin holding considerable promise as a beneficial drug for metastatic melanoma clinical management. It is the proteome navigation that enables systemic biomarkering and targeted drugging to open new therapeutic windows for advanced disease.
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The actin nucleation factors JMY and WHAMM enable a rapid Arp2/3 complex-mediated intrinsic pathway of apoptosis. PLoS Genet 2021; 17:e1009512. [PMID: 33872315 PMCID: PMC8084344 DOI: 10.1371/journal.pgen.1009512] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 04/29/2021] [Accepted: 03/28/2021] [Indexed: 01/02/2023] Open
Abstract
The actin cytoskeleton is a well-known player in most vital cellular processes, but comparably little is understood about how the actin assembly machinery impacts programmed cell death pathways. In the current study, we explored roles for the human Wiskott-Aldrich Syndrome Protein (WASP) family of actin nucleation factors in DNA damage-induced apoptosis. Inactivation of each WASP-family gene revealed that two of them, JMY and WHAMM, are necessary for rapid apoptotic responses. JMY and WHAMM participate in a p53-dependent cell death pathway by enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation. JMY-mediated apoptosis requires actin nucleation via the Arp2/3 complex, and actin filaments are assembled in cytoplasmic territories containing clusters of cytochrome c and active caspase-3. The loss of JMY additionally results in significant changes in gene expression, including upregulation of the WHAMM-interacting G-protein RhoD. Depletion or deletion of RHOD increases cell death, suggesting that RhoD normally contributes to cell survival. These results give rise to a model in which JMY and WHAMM promote intrinsic cell death responses that can be opposed by RhoD.
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The multiple roles of actin-binding proteins at invadopodia. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021. [PMID: 33962752 DOI: 10.1016/bs.ircmb.2021.03.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
Invadopodia are actin-rich membrane protrusions that facilitate cancer cell dissemination by focusing on proteolytic activity and clearing paths for migration through physical barriers, such as basement membranes, dense extracellular matrices, and endothelial cell junctions. Invadopodium formation and activity require spatially and temporally regulated changes in actin filament organization and dynamics. About three decades of research have led to a remarkable understanding of how these changes are orchestrated by sequential recruitment and coordinated activity of different sets of actin-binding proteins. In this chapter, we provide an update on the roles of the actin cytoskeleton during the main stages of invadopodium development with a particular focus on actin polymerization machineries and production of pushing forces driving extracellular matrix remodeling.
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Dziengelewski C, Rodrigue MA, Caillier A, Jacquet K, Boulanger MC, Bergeman J, Fuchs M, Lambert H, Laprise P, Richard DE, Bordeleau F, Huot MÉ, Lavoie JN. Adenoviral protein E4orf4 interacts with the polarity protein Par3 to induce nuclear rupture and tumor cell death. J Cell Biol 2020; 219:151580. [PMID: 32328642 PMCID: PMC7147092 DOI: 10.1083/jcb.201805122] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 12/12/2019] [Accepted: 02/04/2020] [Indexed: 12/15/2022] Open
Abstract
The tumor cell–selective killing activity of the adenovirus type 2 early region 4 ORF4 (E4orf4) protein is poorly defined at the molecular level. Here, we show that the tumoricidal effect of E4orf4 is typified by changes in nuclear dynamics that depend on its interaction with the polarity protein Par3 and actomyosin contractility. Mechanistically, E4orf4 induced a high incidence of nuclear bleb formation and repetitive nuclear ruptures, which promoted nuclear efflux of E4orf4 and loss of nuclear integrity. This process was regulated by nucleocytoskeletal connections, Par3 clustering proximal to nuclear lamina folds, and retrograde movement of actin bundles that correlated with nuclear ruptures. Significantly, Par3 also regulated the incidence of spontaneous nuclear ruptures facilitated by the downmodulation of lamins. This work uncovered a novel role for Par3 in controlling the actin-dependent forces acting on the nuclear envelope to remodel nuclear shape, which might be a defining feature of tumor cells that is harnessed by E4orf4.
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Affiliation(s)
- Claire Dziengelewski
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada
| | - Marc-Antoine Rodrigue
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada
| | - Alexia Caillier
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada
| | - Kévin Jacquet
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada
| | - Marie-Chloé Boulanger
- Department of Surgery, Quebec Heart and Lung Institute/Research Center, Université Laval, Québec, Canada
| | - Jonathan Bergeman
- Institut de Recherches Clinique de Montréal, Montréal, Québec, Canada
| | - Margit Fuchs
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Faculty of Management, Dalhousie University, Halifax, Canada
| | - Herman Lambert
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada
| | - Patrick Laprise
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada.,Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Université Laval, Québec City, Québec, Canada
| | - Darren E Richard
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Université Laval, Québec City, Québec, Canada.,Endocrinology and Nephrology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada
| | - François Bordeleau
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada.,Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Université Laval, Québec City, Québec, Canada
| | - Marc-Étienne Huot
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada.,Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Université Laval, Québec City, Québec, Canada
| | - Josée N Lavoie
- Centre de Recherche sur le Cancer de l'Université Laval, Québec City, Québec, Canada.,Oncology, Centre de Recherche du CHU de Québec-Université Laval, Québec City, Québec, Canada.,Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Université Laval, Québec City, Québec, Canada
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Pezzella F, Ribatti D. Vascular co-option and vasculogenic mimicry mediate resistance to antiangiogenic strategies. Cancer Rep (Hoboken) 2020; 5:e1318. [PMID: 33295149 PMCID: PMC9780428 DOI: 10.1002/cnr2.1318] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 10/13/2020] [Accepted: 10/21/2020] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND The concept that all the tumors need the formation of new vessels to grow inspired the hypothesis that inhibition of angiogenesis would have led to "cure" cancer. The expectancy that this type of therapy would have avoided the insurgence of resistance was based on the concept that targeting normal vessels, instead of the cancer cells which easily develop new mutations, would have allowed evasion of drug caused selection is, however, more complex as it was made apparent by the discovery of nonangiogenic tumors. At the same time an increasing number of trials with antiangiogenic drugs were coming out as not as successful as expected, mostly because of the appearance of unexpected resistance. RECENT FINDINGS Among the several different mechanisms of resistance to antiangiogenic treatment by now described, we review the evidences that vascular co-option and vasculogenic mimicry by nonangiogenic tumors are effectively two of such mechanisms. We focused on reviewing exclusively the study, both clinical and preclinical, that offer a demonstration that vascular co-option and vasculogenic mimicry are effectively two mechanisms of both intrinsic and acquired resistance. CONCLUSION The discovery that vascular co-opting and vasculogenic mimicry are two ways of escaping antiangiogenic treatment, prompts the need for a better understanding of this phenomenon in order to improve cancer treatment.
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Affiliation(s)
- Francesco Pezzella
- Nuffield Division of Laboratory Science, Radcliffe Department of MedicineJohn Radcliffe Hospital, University of OxfordOxfordUK
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory OrgansUniversity of Bari Medical SchoolBariItaly
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Liu YJ, Zhang T, Cheng D, Yang J, Chen S, Wang X, Li X, Duan D, Lou H, Zhu L, Luo J, Ho MS, Wang XD, Duan S. Late endosomes promote microglia migration via cytosolic translocation of immature protease cathD. SCIENCE ADVANCES 2020; 6:6/50/eaba5783. [PMID: 33298434 PMCID: PMC7725477 DOI: 10.1126/sciadv.aba5783] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 10/26/2020] [Indexed: 06/12/2023]
Abstract
Organelle transport requires dynamic cytoskeleton remodeling, but whether cytoskeletal dynamics are, in turn, regulated by organelles remains elusive. Here, we demonstrate that late endosomes, a type of prelysosomal organelles, facilitate actin-cytoskeleton remodeling via cytosolic translocation of immature protease cathepsin D (cathD) during microglia migration. After cytosolic translocation, late endosome-derived cathD juxtaposes actin filaments at the leading edge of lamellipodia. Suppressing cathD expression or blocking its cytosolic translocation impairs the maintenance but not the initiation of lamellipodial extension. Moreover, immature cathD balances the activity of the actin-severing protein cofilin to maintain globular-actin (G-actin) monomer pool for local actin recycling. Our study identifies cathD as a key lysosomal molecule that unconventionally contributes to actin cytoskeleton remodeling via cytosolic translocation during adenosine triphosphate-evoked microglia migration.
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Affiliation(s)
- Yi-Jun Liu
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Ting Zhang
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Daxiao Cheng
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Junhua Yang
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Sicong Chen
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Xingyue Wang
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xia Li
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Duo Duan
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Huifang Lou
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Liya Zhu
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jianhong Luo
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Margaret S Ho
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
| | - Xiao-Dong Wang
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.
- Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Shumin Duan
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.
- Mental Health Center, Zhejiang University School of Medicine, Hangzhou, China
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Fan X, Li Y, Yi X, Chen G, Jin S, Dai Y, Cui B, Dai B, Lin H, Zhou D. Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients. Neoplasia 2020; 22:630-643. [PMID: 33059309 PMCID: PMC7566847 DOI: 10.1016/j.neo.2020.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022] Open
Abstract
Aberrant methylation is a hallmark of hepatocellular carcinoma and plays an important role in tumor initiation and progression. However, the epigenome-wide methylation patterns of portal vein tumor thrombosis (PVTTs) have not been fully explored. Here, we performed epigenome-wide DNA methylation of adjacent normal tissues (ANTs), paired tumor tissues and paired PVTTs using an Infinium HumanMethylation450 array (n = 11) and conducted the Sequenom EpiTYPER assays to confirm the aberrantly methylated genes. MTS and apoptosis assay were used to assess the synergistic effect of two drugs on the HCC cell lines. We found the mean global methylation levels of HCC tissues and PVTTs were significantly lower than ANTs (P < 0.01). A total of 864 differentially methylated CpG sites annotated in 532 genes were identified between HCC tissues and paired PVTTs (|mean methylation difference|>10%, P < 0.005). The pathway analysis based on hypermethylated genes in PVTT tissues was interestingly enriched in regulation of actin cytoskeleton pathway (P = 4.48E−5). We found 23 genes whose methylation levels were gradually alternated in HCC tissues and PVTTs. Aberrant methylation status of TNFRSF10A, ZC3H3 and SLC9A3R2 were confirmed in a validation cohort (n = 48). The functional experiments demonstrated the combination of decitabine (DAC) and tumor necrosis factor-related apoptosis-inducing ligand (rh-TRAIL) could synergistically suppress the proliferation and induce apoptosis in SK-Hep-1 and Huh7 cell lines. Together, our findings indicated that DNA methylation plays an important role in the PVTT formation through regulating the metastasis-related pathways. The combination of DAC and rh-TRAIL might be a promising treatment strategy for HCC.
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Affiliation(s)
- Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xin Yi
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Guoqiao Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yili Dai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bin Cui
- College of Life Science and Technology, Nanyang Normal University, Nanyang, China
| | - Binghua Dai
- Department of Special Treatment Ⅰ and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Daizhan Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, Shanghai Jiao Tong University, Shanghai, China.
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Park KC, Paluncic J, Kovacevic Z, Richardson DR. Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer. Free Radic Biol Med 2020; 157:154-175. [PMID: 31132412 DOI: 10.1016/j.freeradbiomed.2019.05.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/24/2019] [Accepted: 05/16/2019] [Indexed: 12/18/2022]
Abstract
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that is regulated by hypoxia, metal ions including iron, the free radical nitric oxide (NO.), and various stress stimuli. This intriguing molecule exhibits diverse functions in cancer, inhibiting epithelial-mesenchymal transition (EMT), cell migration and angiogenesis by modulation of a plethora of oncogenes via cellular signaling. Thus, pharmacological targeting of NDRG1 signaling in cancer is a promising therapeutic strategy. Of note, novel anti-tumor agents of the di-2-pyridylketone thiosemicarbazone series, which exert the "double punch" mechanism by binding metal ions to form redox-active complexes, have been demonstrated to markedly up-regulate NDRG1 expression in cancer cells. This review describes the mechanisms underlying NDRG1 modulation by the thiosemicarbazones and the diverse effects NDRG1 exerts in cancer. As a major induction mechanism, iron depletion appears critical, with NO. also inducing NDRG1 through its ability to bind iron and generate dinitrosyl-dithiol iron complexes, which are then effluxed from cells. Apart from its potent anti-metastatic role, several studies have reported a pro-oncogenic role of NDRG1 in a number of cancer-types. Hence, it has been suggested that NDRG1 plays pleiotropic roles depending on the cancer-type. The molecular mechanism(s) underlying NDRG1 pleiotropy remain elusive, but are linked to differential regulation of WNT signaling and potentially differential interaction with the tumor suppressor, PTEN. This review discusses NDRG1 induction mechanisms by metal ions and NO. and both the anti- and possible pro-oncogenic functions of NDRG1 in multiple cancer-types and compares the opposite effects this protein exerts on cancer progression.
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Affiliation(s)
- Kyung Chan Park
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Jasmina Paluncic
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia.
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia.
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J J, Vanisree AJ. Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. Ann Neurosci 2020; 27:114-123. [PMID: 34556949 PMCID: PMC8455008 DOI: 10.1177/0972753120950057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Background: Glioma, the most common form of a malignant brain tumour is characterised by a poor prognosis, which is attributable to its resistance against current therapeutic approaches. Temozolomide (TMZ), a DNA alkylating agent, is the first-line drug for glioma treatment. Long-term treatment using TMZ was reported to culminate in the development of resistance with overexpression of multidrug resistance 1 gene coded protein P-glycoprotein, which in turn releases the drugs from the tumour cells. Purpose: Thus, to circumvent such resistance issues, the current study attempted to explore the effect of naringenin (a flavanone) with proven antiglial tumour potential, in mitigating the features of TMZ resistance. Methods: Colony-forming assay, invasion assay and scratch wound assay were performed among the groups, namely tumour control (C6), vehicle control (V), naringenin (NGEN)-treated, drug-resistant tumour cells (C6R), and drug resistance cells added with NGEN (C6R+NGEN), to examine the impact of NGEN on migration and invasion. The effect of NGEN on filopodia length and density during cell migration was also studied in addition to the matrix metalloproteinases (MMP-2 and MMP-9) and p-ERK levels. Results and Conclusion: NGEN and C6R+NGEN groups had shown significant reduction (P < .01) in length and density of filopodia, colony formation, invasion and wound healing. Further, NGEN could also modify the assessed protein levels (P < .001), which were involved in migration and invasion in sensitive and resistant cells. Our study had provided the first evidence on NGEN-induced enhanced sensitivity against TMZ resistance with profound influence as an antimigratory and anti-invasive agent.
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Affiliation(s)
- Jayalakshmi J
- Department of Biochemistry, University of Madras, Chennai, Tamil Nadu, India
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Cheng Y, Felix B, Othmer HG. The Roles of Signaling in Cytoskeletal Changes, Random Movement, Direction-Sensing and Polarization of Eukaryotic Cells. Cells 2020; 9:E1437. [PMID: 32531876 PMCID: PMC7348768 DOI: 10.3390/cells9061437] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 12/21/2022] Open
Abstract
Movement of cells and tissues is essential at various stages during the lifetime of an organism, including morphogenesis in early development, in the immune response to pathogens, and during wound-healing and tissue regeneration. Individual cells are able to move in a variety of microenvironments (MEs) (A glossary of the acronyms used herein is given at the end) by suitably adapting both their shape and how they transmit force to the ME, but how cells translate environmental signals into the forces that shape them and enable them to move is poorly understood. While many of the networks involved in signal detection, transduction and movement have been characterized, how intracellular signals control re-building of the cyctoskeleton to enable movement is not understood. In this review we discuss recent advances in our understanding of signal transduction networks related to direction-sensing and movement, and some of the problems that remain to be solved.
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Affiliation(s)
- Yougan Cheng
- Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA;
| | - Bryan Felix
- School of Mathematics, University of Minnesota, Minneapolis, MN 55445, USA;
| | - Hans G. Othmer
- School of Mathematics, University of Minnesota, Minneapolis, MN 55445, USA;
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Fujiwara K, Yazama H, Donishi R, Koyama S, Fukuhara T, Kitatani K, Kataoka H, Takeuchi H. C 6-ceramide Inhibits the Motility of Anaplastic Thyroid Carcinoma Cells. Yonago Acta Med 2020; 63:95-98. [PMID: 32494214 DOI: 10.33160/yam.2020.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 03/04/2020] [Indexed: 11/05/2022]
Abstract
Background Anaplastic thyroid carcinoma (ATC) is an aggressive type of thyroid cancer, and its metastasis requires cell motility. Ceramide is involved in a variety of biological processes, including inflammation, cell signaling, cell motility, and induction of apoptosis, however has not previously been reported to inhibit the motility of ATC cells. We evaluated the effect of short chain C6-ceramide on motility of ATC cells. Methods Cell motility of 8305C thyroid carcinoma cell line treated with C6-ceramide was assessed using a transwell migration assay and a pseudopodia formation assay. Results Treatment with 10 µM C6-ceramide resulted in significantly fewer migratory cells than control treatment in a transwell migration assay (P < 0.002). In condition medium, 82.6% of C6-ceramide-treated cells formed lamellipodia. Importantly, treatment with 10 µM C6-ceramide drastically decreased the number of cells forming lamellipodia by 17.6% (P < 0.01). Conclusion Our results suggest that treatment with a low concentration of ceramide may prevent metastasis and recurrence of ATC by inhibiting cell motility. Further studies are necessary to investigate the mechanism of inhibition of cell motility by ceramide. Ceramide shows promise as a therapeutic treatment for ATC.
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Affiliation(s)
- Kazunori Fujiwara
- Division of Otolaryngology, Head and Neck Surgery, Department of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Hiroaki Yazama
- Division of Otolaryngology, Head and Neck Surgery, Department of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Ryohei Donishi
- Division of Otolaryngology, Head and Neck Surgery, Department of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Satoshi Koyama
- Division of Otolaryngology, Head and Neck Surgery, Department of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Takahiro Fukuhara
- Division of Otolaryngology, Head and Neck Surgery, Department of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Kazuyuki Kitatani
- Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata 573-0101, Japan
| | - Hideyuki Kataoka
- Division of Otolaryngology, Head and Neck Surgery, Department of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
| | - Hiromi Takeuchi
- Division of Otolaryngology, Head and Neck Surgery, Department of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan
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Li T, Liu X, Xu B, Wu W, Zang Y, Li J, Wei L, Qian Y, Xu H, Xie M, Wang Q, Wang L. SKA1 regulates actin cytoskeleton remodelling via activating Cdc42 and influences the migration of pancreatic ductal adenocarcinoma cells. Cell Prolif 2020; 53:e12799. [PMID: 32232899 PMCID: PMC7162805 DOI: 10.1111/cpr.12799] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/08/2020] [Accepted: 03/04/2020] [Indexed: 12/29/2022] Open
Abstract
Objectives Spindle and kinetochore–associated protein 1(SKA1), originally identified as a protein essential for proper chromosome segregation, has been recently linked to multiple malignancies. This study aimed to explore the biological, clinical role and molecular mechanism of SKA1 in pancreatic carcinogenesis. Materials and Methods SKA1 expression was detected in 145 pancreatic ductal adenocarcinoma (PDAC) specimens by immunohistochemistry. Biological behaviour assays were used to determine the role of SKA1 in PDAC progression in vitro and in vivo. Using isobaric tags for relative and absolute quantitation (iTRAQ), SKA1’s downstream proteins were examined. Moreover, cytochalasin B and ZCL278 were used to explore the changes of SKA1‐induced signalling and cell morphology, with further confirmation by immunoblotting and immunofluorescence assays. Results Increased SKA1 expression was significantly correlated with tumour size and cellular differentiation degree in PDAC tissues. Furthermore, elevated levels of SKA1 reflected shorter overall survival (P = .019). As for biological behaviour, SKA1 acted as a tumour promotor in PDAC, overexpression of SKA1 facilitates cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, we demonstrated that SKA1 enhanced pancreatic cancer aggressiveness by inhibiting G2/M arrest and regulating actin cytoskeleton organization via activating Cdc42. Conclusions This study revealed novel roles for SKA1 as an important regulator of actin cytoskeleton organization and an oncogene in PDAC cells, which may provide insights into developing novel therapeutics.
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Affiliation(s)
- Tong Li
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Liu
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Xu
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Wu
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Zang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juanjuan Li
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lumin Wei
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuting Qian
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Xu
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingping Xie
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Wang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lifu Wang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Yu Q, Zhang B, Zhang YM, Liu YH, Liu Y. Actin Cytoskeleton-Disrupting and Magnetic Field-Responsive Multivalent Supramolecular Assemblies for Efficient Cancer Therapy. ACS APPLIED MATERIALS & INTERFACES 2020; 12:13709-13717. [PMID: 32118400 DOI: 10.1021/acsami.0c01762] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Actin cytoskeleton disruption is a promising and intriguing anticancer strategy, but their efficiency is frequently compromised by severe side effects of the actin cytoskeleton-disrupting agents. In this study, we constructed the biocompatible actin cytoskeleton-targeting multivalent supramolecular assemblies that specifically target and disrupt the tumor actin cytoskeleton for cancer therapy. The assemblies were composed of β-cyclodextrin-grafted hyaluronic acid (HACD) and iron oxide magnetic nanoparticles (MNPs) grafted by an actin-binding peptide (ABP) and adamantane (Ada)-modified polylysine. Owing to the multivalent binding between cyclodextrin and Ada, HACD, and peptide-grafted MNPs (MNP-ABP-Ada) could self-assemble to form MNP-ABP-Ada⊂HACD nanofibers in a geomagnetism-dependent manner. Furthermore, the presence of ABP rendered the assemblies to efficiently target the actin cytoskeleton. Interestingly, with the acid of a low-frequency alternating magnetic field (200 Hz), the actin cytoskeleton-targeting nanofibers could induce severe actin disruption, leading to a remarkable cell cycle arrest and drastic cell death of tumor cells both in vitro and in vivo, but showed no obvious toxicity to normal cells. The actin cytoskeleton-targeting/disrupting supramolecular assembly implies an excellent strategy for realizing efficient cancer therapy.
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Affiliation(s)
- Qilin Yu
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Science, Nankai University, Tianjin 300071, P. R. China
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
| | - Bing Zhang
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
| | - Ying-Ming Zhang
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
| | - Yao-Hua Liu
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
| | - Yu Liu
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
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Fu L, Han B, Zhou Y, Ren J, Cao W, Patel G, Kai G, Zhang J. The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients. Front Pharmacol 2020; 11:193. [PMID: 32265690 PMCID: PMC7098175 DOI: 10.3389/fphar.2020.00193] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/11/2020] [Indexed: 12/31/2022] Open
Abstract
Cancer is a common malignant disease worldwide with an increasing mortality in recent years. Salvia miltiorrhiza, a well-known traditional Chinese medicine, has been used for the treatment of cardiovascular and cerebrovascular diseases for thousands of years. The liposoluble tanshinones in S. miltiorrhiza are important bioactive components and mainly include tanshinone IIA, dihydrodanshinone, tanshinone I, and cryptotanshinone. Previous studies showed that these four tanshinones exhibited distinct inhibitory effects on tumor cells through different molecular mechanisms in vitro and in vivo. The mechanisms mainly include the inhibition of tumor cell growth, metastasis, invasion, and angiogenesis, apoptosis induction, cell autophagy, and antitumor immunity, and so on. In this review, we describe the latest progress on the antitumor functions and mechanisms of these four tanshinones to provide a deeper understanding of the efficacy. In addition, the important role of tumor immunology is also reviewed.
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Affiliation(s)
- Li Fu
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Bing Han
- Laboratory of Medicinal Plant Biotechnology, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yang Zhou
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Jie Ren
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Wenzhi Cao
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
| | - Gopal Patel
- Laboratory of Medicinal Plant Biotechnology, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Guoyin Kai
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China.,Laboratory of Medicinal Plant Biotechnology, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jun Zhang
- School of Life Sciences, Institute of Plant Biotechnology, Shanghai Normal University, Shanghai, China
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Gellert M, Richter E, Mostertz J, Kantz L, Masur K, Hanschmann EM, Ribback S, Kroeger N, Schaeffeler E, Winter S, Hochgräfe F, Schwab M, Lillig CH. The cytosolic isoform of glutaredoxin 2 promotes cell migration and invasion. Biochim Biophys Acta Gen Subj 2020; 1864:129599. [PMID: 32173377 DOI: 10.1016/j.bbagen.2020.129599] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/25/2020] [Accepted: 03/10/2020] [Indexed: 02/07/2023]
Abstract
BACKROUND Cytosolic glutaredoxin 2 (Grx2c) controls axonal outgrowth and is specifically induced in many cancer cell lines. We thus hypothesized that Grx2c promotes cell motility and invasiveness. METHODS We characterized the impact of Grx2c expression in cell culture models. We combined stable isotope labeling, phosphopeptide enrichment, and high-accuracy mass spectrometry to characterize the underlying mechanisms. RESULTS The most prominent associations were found with actin dynamics, cellular adhesion, and receptor-mediated signal transduction, processes that are crucial for cell motility. For instance, collapsin response mediator protein 2, a protein involved in the regulation of cytoskeletal dynamics, is regulated by Grx2c through a redox switch that controls the phosphorylation state of the protein as well. Cell lines expressing Grx2c showed dramatic alterations in morphology. These cells migrated two-fold faster and gained the ability to infiltrate a collagen matrix. CONCLUSIONS The expression of Grx2c promotes cell migration, and may negatively correlate with cancer-specific survival. GENERAL SIGNIFICANCE Our results imply critical roles of Grx2c in cytoskeletal dynamics, cell adhesion, and cancer cell invasiveness.
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Affiliation(s)
- Manuela Gellert
- Institute for Medical Biochemistry and Molecular Biology, University Medicine, University Greifswald, Germany
| | - Erik Richter
- Competence Center Functional Genomics, Junior Research Group Pathoproteomics, University Greifswald, Germany
| | - Jörg Mostertz
- Competence Center Functional Genomics, Junior Research Group Pathoproteomics, University Greifswald, Germany
| | - Liane Kantz
- Center for Innovation Competence plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Greifswald, Germany
| | - Kai Masur
- Center for Innovation Competence plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Greifswald, Germany
| | - Eva-Maria Hanschmann
- Institute for Medical Biochemistry and Molecular Biology, University Medicine, University Greifswald, Germany
| | | | - Nils Kroeger
- Institute for Medical Biochemistry and Molecular Biology, University Medicine, University Greifswald, Germany; Clinic for Urology, University Medicine Greifswald, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany
| | - Stefan Winter
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany
| | - Falko Hochgräfe
- Competence Center Functional Genomics, Junior Research Group Pathoproteomics, University Greifswald, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Departments of Clinical Pharmacology, and Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany
| | - Christopher Horst Lillig
- Institute for Medical Biochemistry and Molecular Biology, University Medicine, University Greifswald, Germany.
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Mechanics of actin filaments in cancer onset and progress. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 355:205-243. [DOI: 10.1016/bs.ircmb.2020.05.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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50
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Choi J, Lee YJ, Yoon YJ, Kim CH, Park SJ, Kim SY, Doo Kim N, Cho Han D, Kwon BM. Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex. Cancer Sci 2019; 110:3788-3801. [PMID: 31571309 PMCID: PMC6890432 DOI: 10.1111/cas.14205] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/18/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
ARPC2 is a subunit of the Arp2/3 complex, which is essential for lamellipodia, invadopodia and filopodia, and ARPC2 has been identified as a migrastatic target molecule. To identify ARPC2 inhibitors, we generated an ARPC2 knockout DLD-1 human colon cancer cell line using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system and explored gene signature-based strategies, such as a connectivity map (CMap) using the gene expression profiling data of ARPC2 knockout and knockdown cells. From the CMap-based drug discovery strategy, we identified pimozide (a clinically used antipsychotic drug) as a migrastatic drug and ARPC2 inhibitor. Pimozide inhibited the migration and invasion of various cancer cells. Through drug affinity responsive target stability (DARTS) analysis and cellular thermal shift assay (CETSA), it was confirmed that pimozide directly binds to ARPC2. Pimozide increased the lag phase of Arp2/3 complex-dependent actin polymerization and inhibited the vinculin-mediated recruitment of ARPC2 to focal adhesions in cancer cells. To validate the likely binding of pimozide to ARPC2, mutant cells, including ARPC2F225A , ARPC2F247A and ARPC2Y250F cells, were prepared using ARPC2 knockout cells prepared by gene-editing technology. Pimozide strongly inhibited the migration of mutant cells because the mutated ARPC2 likely has a larger binding pocket than the wild-type ARPC2. Therefore, pimozide is a potential ARPC2 inhibitor, and ARPC2 is a new molecular target. Taken together, the results of the present study provide new insights into the molecular mechanism and target that are responsible for the antitumor and antimetastatic activity of pimozide.
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Affiliation(s)
- Jiyeon Choi
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.,Department of Bioscience and Biotechnology, Chungnam National University, Daejeon, Korea
| | - Yu-Jin Lee
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Yae Jin Yoon
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Cheol-Hee Kim
- Department of Bioscience and Biotechnology, Chungnam National University, Daejeon, Korea
| | - Seung-Jin Park
- Korea Research Institute of Bioscience and Biotechnology, Personalized Genomic Medicine Research Center, Daejeon, Korea.,University of Science and Technology, Daejeon, Korea
| | - Seon-Young Kim
- Korea Research Institute of Bioscience and Biotechnology, Personalized Genomic Medicine Research Center, Daejeon, Korea.,University of Science and Technology, Daejeon, Korea
| | - Nam Doo Kim
- Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea
| | - Dong Cho Han
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.,University of Science and Technology, Daejeon, Korea
| | - Byoung-Mog Kwon
- Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.,University of Science and Technology, Daejeon, Korea
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