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Shi R, Farnsworth DA, Febres-Aldana CA, Chow JLM, Sheena R, Atwal T, Gomez Marti JL, Li S, Thomas KN, Lee CM, Awrey SJ, McDonald PC, Somwar R, Dedhar S, Ladanyi M, Bennewith KL, Lockwood WW. Drug tolerance and persistence to EGFR inhibitor treatment are mediated by an ILK-SFK-YAP signaling axis in lung adenocarcinoma. Oncogene 2025:10.1038/s41388-025-03461-6. [PMID: 40450112 DOI: 10.1038/s41388-025-03461-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 05/09/2025] [Accepted: 05/20/2025] [Indexed: 06/03/2025]
Abstract
Combating resistance to targeted therapy remains a major challenge to improving lung cancer care. Epithelial-mesenchymal transition (EMT) in tumour cells is an established non-genetic resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) that is also associated with worse outcome in patients. Here we demonstrate that integrin-linked kinase (ILK) is an important driver of EMT-mediated TKI resistance in lung adenocarcinoma (LUAD) by promoting a drug-tolerant persister (DTP) cell phenotype. Our results indicate that high ILK expression is associated with EMT in LUAD patients and that genetic suppression of ILK can limit EMT progression and reduce the viability of DTP cells by impairing YAP activation, ultimately improving osimertinib (Osi) sensitivity in LUAD cells. Importantly, LUAD cells with high ILK expression are able to persist during EGFR-TKI treatment, acquiring additional genetic and phenotypic alterations to develop EGFR-TKI resistance. To improve clinical translatability of our findings, we showed that pharmacological inhibition of ILK can suppress EMT and improve Osi response in LUAD cells. Lastly, we found that strong immunohistochemistry staining of ILK in patient biopsies was significantly associated with and may be used to predict receptor tyrosine kinase-independent mechanisms of EGFR-TKI resistance. Overall, our results suggest that ILK is an important regulator of EGFR-TKI response and may be exploited as a predictor for acquired resistance, providing evidence for co-targeting ILK with EGFR to better control minimal residual disease and EGFR-TKI resistance in lung cancer.
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Affiliation(s)
- Rocky Shi
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Dylan A Farnsworth
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Christopher A Febres-Aldana
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Justine L M Chow
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Ravinder Sheena
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Tejveer Atwal
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Juan Luis Gomez Marti
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Samantha Li
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Kiersten N Thomas
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Che-Min Lee
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Shannon J Awrey
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Paul C McDonald
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Romel Somwar
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shoukat Dedhar
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
| | - Marc Ladanyi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin L Bennewith
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
- Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - William W Lockwood
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.
- Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
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Wu Y, Guo Z, Li Z, Cai C, Liu J, Tang X, Que L. Effects of Integrin-Linked Kinase Silencing Combined With Trichostatin A on Cancer Stem Cells. Oral Dis 2025. [PMID: 40364491 DOI: 10.1111/odi.15377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/13/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025]
Abstract
OBJECTIVES Oral squamous cell carcinoma (OSCC) is characterized by high invasiveness and metastasis, with cancer stem cells (CSCs) playing a central role in tumor progression. This study investigates the effects of integrin-linked kinase (ILK) silencing and trichostatin A (TSA) treatment on CSCs, assessing their potential to diminish CSC properties and inhibit OSCC progression. METHODS AND MATERIALS CSCs were enriched and isolated from primary OSCC samples and Tca8113 cell line and MOC1 cell line using side population (SP) analysis, with their characteristics and the therapeutic impact of treatments assessed through assays such as MTT, wound healing, cell invasion, cell cycle, and apoptosis. RESULTS Higher SP cell content correlated significantly with poor pathological classification, metastasis, and recurrence. Treated CSCs showed reduced proliferation, migration, and invasion, along with increased apoptosis. In vivo experiments demonstrated that the combined treatment substantially reduced tumor growth. CONCLUSION The study confirms the efficacy of targeting CSCs with ILK silencing and TSA treatment in OSCC, suggesting a promising strategy for CSC-directed therapies that merit further investigation.
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Affiliation(s)
- Yulu Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & 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
| | - Zhiyong Guo
- State Key Laboratory of Oral Diseases & National Center for Stomatology & 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
| | - Zhangao Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Chenchen Cai
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Jiyuan Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & 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
| | - Xiufa Tang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & 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
| | - Lin Que
- State Key Laboratory of Oral Diseases & National Center for Stomatology & 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
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Soni UK, Tripathi R, Sankhwar P, Kumari S, Soni M, Manoj A, Ubba V, Gupta S, Verma RK, Pratap JV, Jha RK. MCP-1 promotes ILK phosphorylation at Ser246 during endometriosis development and affects the pregnancy outcome. Mol Hum Reprod 2025; 31:gaaf004. [PMID: 40037802 DOI: 10.1093/molehr/gaaf004] [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: 05/05/2023] [Revised: 12/21/2024] [Indexed: 03/06/2025] Open
Abstract
In women with endometriosis, monocyte chemoattractant protein 1 (MCP-1) or chemokine (C-C motif) ligand 2 (CCL2) is elevated in serum, peritoneal fluid, and endometriotic lesions, though its exact role in endometriosis is still unknown. The MCP-1 downstream molecule integrin-linked kinase (ILK) is involved in several cellular events. Our recent findings suggest that MCP-1 promotes an inflammatory response via ILK in a mouse endometriosis model. MCP-1 also favors human endometriotic cell aggregation, colonization, migration, and invasion, which are reversed by the ILK inhibitor compound (CPD) 22 (600 nM). Furthermore, the inflammatory response to MCP-1 is reduced by ILK inhibition (CPD22, 20 mg/kg body weight) in a mouse model. We studied MCP-1/chemokine (C-C motif) receptor type (CCR)2-mediated ILK signaling in endometriosis and observed a positive association of ILK and CCR2 with endometriosis in patients. Our immunoprecipitation and molecular docking studies confirmed ILK interaction with CCR2 under a high MCP-1 level in Hs832(C).TCs (human endometriotic cells). MCP-1 promotes ILK-Ser246 phosphorylation in endometriotic cells in human and mouse models. The mouse model shows the same inflammatory markers as seen in human endometriosis and mimics some of the aspects of the inflammatory reaction. Targeting ILK by CDP22 (20 mg/kg) suppresses endometriosis progression in the mouse model. Altered MCP-1-ILK signaling leads to poor pregnancy outcomes in the mouse model. Further, our in silico results suggest that CPD22 stabilizes the interaction with Asp234 and His318 residues of ILK and inhibits the Ser246 phosphorylation. In conclusion, MCP-1 activates ILK at the Ser246 residue and leads to lesion development/progression, reflecting the therapeutic importance of ILK for endometriosis management through the mouse model.
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Affiliation(s)
- Upendra Kumar Soni
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rupal Tripathi
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
| | - Pushplata Sankhwar
- Department of Obstetrics and Gynecology, King George's Medical University, Lucknow, India
| | - Suparna Kumari
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
| | - Mohini Soni
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Anveshika Manoj
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Vaibhave Ubba
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Satish Gupta
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
| | - Raj Kumar Verma
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
| | - J Venkatesh Pratap
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rajesh Kumar Jha
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre, (CSIR-HRDC) Campus, Ghaziabad, India
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Jung SH, Lee SE, Yun S, Min DE, Shin Y, Chung YJ, Lee SH. Different inflammatory, fibrotic, and immunological signatures between pre-fibrotic and overt primary myelofibrosis. Haematologica 2025; 110:938-951. [PMID: 39385733 PMCID: PMC11959246 DOI: 10.3324/haematol.2024.285598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 09/27/2024] [Indexed: 10/12/2024] Open
Abstract
Primary myelofibrosis (PMF) is a myeloid proliferative neoplasm (MPN) characterized by bone marrow fibrosis. Pre-fibrotic PMF (pre-PMF) progresses to overt PMF. Megakaryocytes play a primary role in PMF; however, the functions of megakaryocyte subsets and those of other hematopoietic cells during PMF progression remain unclear. We, therefore, analyzed bone marrow aspirates in cases of pre-PMF, overt PMF, and other MPN using single-cell RNA sequencing. We identified 14 cell types with subsets, including hematopoietic stem and progenitor cells (HSPC) and megakaryocytes. HSPC in overt PMF were megakaryocyte-biased and inflammation/fibrosis-enriched. Among megakaryocytes, the epithelial-mesenchymal transition (EMT)-enriched subset was abruptly increased in overt PMF. Megakaryocytes in non-fibrotic/non-PMF MPN were megakaryocyte differentiation-enriched, whereas those in fibrotic/non-PMF MPN were inflammation/fibrosis-enriched. Overall, the inflammation/fibrosis signatures of the HSPC, megakaryocyte, and CD14+ monocyte subsets increased from pre-PMF to overt PMF. Cytotoxic and dysfunctional scores also increased in T and NK cells. Clinically, megakaryocyte and HSPC subsets with high inflammation/fibrosis signatures were frequent in the patients with peripheral blood blasts ≥1%. Single-cell RNA-sequencing predicted higher cellular communication of megakaryocyte differentiation, inflammation/fibrosis, immunological effector/dysfunction, and tumor-associated signaling in overt PMF than in pre-PMF. However, no decisive subset emerged during PMF progression. Our study demonstrated that HSPC, monocytes, and lymphoid cells contribute to the progression of PMF, and subset specificity existed regarding inflammation/fibrosis and immunological dysfunction. PMF progression may depend on alterations of multiple cell types, and EMT-enriched megakaryocytes may be potential targets for diagnosing and treating the progression.
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Affiliation(s)
- Seung-Hyun Jung
- Departments of Biochemistry; Departments of Precision Medicine Research Center/Integrated Research Center for Genome Polymorphism; Departments of Medical Sciences.
| | | | | | | | - Youngjin Shin
- Departments of Basic Medical Science Facilitation Program
| | - Yeun-Jun Chung
- Departments of Precision Medicine Research Center/Integrated Research Center for Genome Polymorphism; Departments of Medical Sciences; Departments of Basic Medical Science Facilitation Program; Departments of Microbiology.
| | - Sug Hyung Lee
- Departments of Medical Sciences; Departments of Cancer Evolution Research Center; Departments of Pathology, College of Medicine, The Catholic University of Korea, Seoul.
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Liu Z, Zhang X, Ben T, Li M, Jin Y, Wang T, Song Y. Focal adhesion in the tumour metastasis: from molecular mechanisms to therapeutic targets. Biomark Res 2025; 13:38. [PMID: 40045379 PMCID: PMC11884212 DOI: 10.1186/s40364-025-00745-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/11/2025] [Indexed: 03/09/2025] Open
Abstract
The tumour microenvironment is the "hotbed" of tumour cells, providing abundant extracellular support for growth and metastasis. However, the tumour microenvironment is not static and is constantly remodelled by a variety of cellular components, including tumour cells, through mechanical, biological and chemical means to promote metastasis. Focal adhesion plays an important role in cell-extracellular matrix adhesion. An in-depth exploration of the role of focal adhesion in tumour metastasis, especially their contribution at the biomechanical level, is an important direction of current research. In this review, we first summarize the assembly of focal adhesions and explore their kinetics in tumour cells. Then, we describe in detail the role of focal adhesion in various stages of tumour metastasis, especially its key functions in cell migration, invasion, and matrix remodelling. Finally, we describe the anti-tumour strategies targeting focal adhesion and the current progress in the development of some inhibitors against focal adhesion proteins. In this paper, we summarize for the first time that focal adhesion play a positive feedback role in pro-tumour metastatic matrix remodelling by summarizing the five processes of focal adhesion assembly in a multidimensional way. It is beneficial for researchers to have a deeper understanding of the role of focal adhesion in the biological behaviour of tumour metastasis and the potential of focal adhesion as a therapeutic target, providing new ideas for the prevention and treatment of metastases.
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Affiliation(s)
- Zonghao Liu
- Department of Radiotherapy, Cancer Hospital of China Medical University, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, P. R. China
- The First Clinical College, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Xiaofang Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Tianru Ben
- The First Clinical College, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Mo Li
- Department of Breast Surgery, Liaoning Cancer Hospital and Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, P. R. China
| | - Yi Jin
- Department of Breast Surgery, Liaoning Cancer Hospital and Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, P. R. China
| | - Tianlu Wang
- Department of Radiotherapy, Cancer Hospital of China Medical University, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, P. R. China.
- Department of Radiotherapy, Cancer Hospital of Dalian University of Technology, Shenyang, Liaoning Province, 110042, People's Republic of China.
- Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning Province, 116024, P. R. China.
| | - Yingqiu Song
- Department of Radiotherapy, Cancer Hospital of China Medical University, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, P. R. China.
- Department of Radiotherapy, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, P. R. China.
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Yu XX, Liu Y, Luo RJ, Song ZX, Chen WK, Mo ZM, Wang FJ. Bioinformatics analysis combined with experimental validation reveals the biological role of the ILK gene in prostate cancer. Discov Oncol 2025; 16:106. [PMID: 39890647 PMCID: PMC11785868 DOI: 10.1007/s12672-025-01852-5] [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: 08/18/2024] [Accepted: 01/24/2025] [Indexed: 02/03/2025] Open
Abstract
BACKGROUND Prostate cancer (PCa) is a prevalent urological malignancy. The integrin-linked kinase (ILK) gene has been identified as an oncogenic driver in hormonal cancers, including PCa. METHODS To identify key genes in PCa, we utilized differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The ILK gene was silenced using short interfering RNA (siRNA), and subsequent experiments focusing on cellular functionality were conducted to evaluate its impact on cell proliferation, apoptosis, and cell cycle. We examined the expression of autophagy-related and cell cycle-related proteins, including MAP1LC3A, BECN1, C-MYC, TP53, and MDM2. Moreover, we conducted Mfuzz expression pattern clustering analysis, gene set enrichment analysis (GSEA), immune function analysis, transcription factor (TF) analysis, and drug prediction. RESULTS 544 significant genes were identified by WGCNA. The protein-protein interaction (PPI) network analysis revealed that MYC was the central regulatory gene, with the intersected genes mainly involved in regulating cell adhesion and drug metabolism in prostate cancer (PCa). Experimental results showed LNCaP cell proliferation was significantly inhibited in the knockdown groups (P < 0.001). Moreover, ILK silencing increased apoptosis in LNCaP cells compared to normal cells and empty vectors, and transfected LNCaP cells were arrested in the S phase of the cell cycle. Notably, C-MYC expression decreased following ILK silencing. Subsequently, we further identified ILK-related regulatory biomarkers. CONCLUSIONS The ILK is an oncogene mainly through influencing the C-MYC in PCa. Inhibition of ILK expression would be a promising method for treating the development and progression of PCa.
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Affiliation(s)
- Xiao-Xiang Yu
- Department of Urology, The 923, Hospital of Chinese People's Liberation Army, Nanning, 530021, Guangxi, China.
| | - Yi Liu
- Department of Urology, The 923, Hospital of Chinese People's Liberation Army, Nanning, 530021, Guangxi, China
| | - Rong-Jiang Luo
- Department of Urology, The 923, Hospital of Chinese People's Liberation Army, Nanning, 530021, Guangxi, China
| | - Zi-Xuan Song
- Department of Urology, The 923, Hospital of Chinese People's Liberation Army, Nanning, 530021, Guangxi, China
| | - Wen-Kai Chen
- Department of Urology, The 923, Hospital of Chinese People's Liberation Army, Nanning, 530021, Guangxi, China
| | - Zeng-Mi Mo
- Department of Urology, The 923, Hospital of Chinese People's Liberation Army, Nanning, 530021, Guangxi, China
| | - Feng-Jing Wang
- Department of Urology, The 923, Hospital of Chinese People's Liberation Army, Nanning, 530021, Guangxi, China
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Katoh K. Signal Transduction Mechanisms of Focal Adhesions: Src and FAK-Mediated Cell Response. FRONT BIOSCI-LANDMRK 2024; 29:392. [PMID: 39614431 DOI: 10.31083/j.fbl2911392] [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: 06/17/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 12/01/2024]
Abstract
Cell-to-substrate adhesion sites, also known as focal adhesion sites (FAs), are complexes of different proteins on the cell surface. FAs play important roles in communication between cells and the extracellular matrix (ECM), leading to signal transduction involving different proteins that ultimately produce the cell response. This cell response involves cell adhesion, migration, motility, cell survival, and cell proliferation. The most important component of FAs are integrins. Integrins are transmembrane proteins that receive signals from the ECM and communicate them to the cytoplasm, thus activating several downstream proteins in a signaling cascade. Cellular Proto-oncogene tyrosine-protein kinase Src (c-Src) and focal adhesion kinase (FAK) are non-receptor tyrosine kinases that functionally interact to promote crucial roles in FAs. c-Src is a tyrosine kinase, activated by autophosphorylation and, in turn, activates another important protein, FAK. Activated FAK directly interacts with the cytoplasmic domain of integrin and activates other FA proteins by attaching to them. These proteins activated by FAK then activate other downstream pathways such as mitogen-activated protein kinase (MAPK) and Akt pathways involved in cell proliferation, migration, and cell survival. Src can induce detachment of FAK from the integrin to increase the focal adhesion turnover. As a result, the Src-FAK complex in FAs is critical for cell adhesion and survival mechanisms. Overexpression of FA proteins has been linked to a variety of pathological disorders, including cancers, growth retardation, and bone deformities. FAK and Src are overexpressed in various cancers. This review, which focuses on the roles of two important signaling proteins, c-Src and FAK, attempts to provide a thorough and up-to-date examination of the signal transduction mechanisms mediated by focal adhesions. The author also described that FAK and Src may serve as potential targets for future therapies against diseases associated with their overexpression, such as certain types of cancer.
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Affiliation(s)
- Kazuo Katoh
- Laboratory of Human Anatomy and Cell Biology, Faculty of Health Sciences, Tsukuba University of Technology, 305-8521 Tsukuba, Japan
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Li J, Zhang W, Chen L, Wang X, Liu J, Huang Y, Qi H, Chen L, Wang T, Li Q. Targeting extracellular matrix interaction in gastrointestinal cancer: Immune modulation, metabolic reprogramming, and therapeutic strategies. Biochim Biophys Acta Rev Cancer 2024; 1879:189225. [PMID: 39603565 DOI: 10.1016/j.bbcan.2024.189225] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/17/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024]
Abstract
The extracellular matrix (ECM) is a major constituent of the tumor microenvironment, acting as a mediator that supports the progression of gastrointestinal (GI) cancers, particularly in mesenchymal subtypes. Beyond providing structural support, the ECM actively shapes the tumor microenvironment (TME) through complex biochemical and biomechanical remodeling. Dysregulation of ECM composition and signaling is closely linked to increased cancer aggressiveness, poor prognosis, and resistance to therapy. ECM components, such as collagen, fibronectin, laminin, and periostin, influence tumor growth, metastasis, immune modulation, and metabolic reprogramming by interacting with tumor cells, immune cells, and cancer-associated fibroblasts. In this review, we highlight the heterogeneous nature of the ECM and the dualistic roles of its components across GI cancers, with a focus on their contributions to immune evasion and metabolic remodeling via intercellular interactions. Additionally, we explore therapeutic strategies targeting ECM remodeling and ECM-centered interactions, emphasizing their potential in enhancing existing anti-tumor therapies.
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Affiliation(s)
- Jiyifan Li
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenxin Zhang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Chen
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinhai Wang
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiafeng Liu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxin Huang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Huijie Qi
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Li Chen
- Department of Pharmacy, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
| | - Tianxiao Wang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
| | - Qunyi Li
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
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Soni UK, Tripathi R, Jha RK. MCP-1 exerts the inflammatory response via ILK activation during endometriosis pathogenesis. Life Sci 2024; 353:122902. [PMID: 39004271 DOI: 10.1016/j.lfs.2024.122902] [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: 09/29/2023] [Revised: 06/18/2024] [Accepted: 07/06/2024] [Indexed: 07/16/2024]
Abstract
AIMS MCP-1 has been shown to be elevated in endometriosis. ILK functions in several cellular events and interacts with MCP-1-signaling. In the current study, we evaluated the role of MCP-1-ILK signaling in human endometriotic cell's (Hs832(C).TCs) potential for colonization, invasion, adhesion, etc. and differentiation of macrophage along with inflammation in an endometriosis mouse model. MATERIALS AND METHODS A mouse model of endometriosis with elevated levels of MCP-1 was developed by injecting MCP-1. We examined the migration, adhesion, colonization and invasion of Hs832(C).TCs in response to MCP-1-ILK signaling. We also examined the differentiation of THP-1 cells to macrophage in response to MCP-1-ILK signaling. KEY FINDINGS We observed that MCP-1 increased Ser246 phosphorylation of ILK in Hs832(C).TCs and enhanced the migration, adhesion, colonization, and invasion of Hs832(C).TCs. In the mouse model of endometriosis, we found elevated chemokines (CCL-11, CCL-22 and CXCL13) levels. An increased level of MCP-1 mediated ILK activation, leading to increased inflammatory reaction and infiltration of residential and circulatory macrophages, and monocyte differentiation, but suppressed the anti-inflammatory reaction. The inhibitor (CPD22) of ILK reversed the MCP-1-mediated action by restoring Hs832(C).TCs and THP-1 phenotype. ILK inhibition in a mouse model of endometriosis reduced the effects of MCP-1 mediated pro-inflammatory cytokines, but increased anti-inflammatory response along with T-regulatory and T-helper cell restoration. SIGNIFICANCE Targeting ILK restores MCP-1 milieu in the peritoneal cavity and endometrial tissues, reduces the inflammatory response, improves the T-regulatory and T-helper cells in the endometriosis mouse model and decreases the migration, adhesion, colonization and invasion of endometriotic cells.
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Affiliation(s)
- Upendra Kumar Soni
- Endocrinology Division, Council of Scientific and Industrial; Research (CSIR)-Central Drug Research Institute (CDRI), Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, U.P., India
| | - Rupal Tripathi
- Endocrinology Division, Council of Scientific and Industrial; Research (CSIR)-Central Drug Research Institute (CDRI), Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rajesh Kumar Jha
- Endocrinology Division, Council of Scientific and Industrial; Research (CSIR)-Central Drug Research Institute (CDRI), Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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10
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Ishii T, Kaya M, Muroi Y. Oral Administration of Probiotic Bifidobacterium breve Ameliorates Tonic-Clonic Seizure in a Pentylenetetrazole-Induced Kindling Mouse Model via Integrin-Linked Kinase Signaling. Int J Mol Sci 2024; 25:9259. [PMID: 39273208 PMCID: PMC11395544 DOI: 10.3390/ijms25179259] [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: 08/02/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Epilepsy is a chronic neurological disorder characterized by recurrent seizures that affects over 70 million people worldwide. Although many antiepileptic drugs that block seizures are available, they have little effect on preventing and curing epilepsy, and their side effects sometimes lead to serious morbidity. Therefore, prophylactic agents with anticonvulsant properties and no adverse effects need to be identified. Recent studies on probiotic administration have reported a variety of beneficial effects on the central nervous system via the microbiota-gut-brain axis. In this study, we investigated the effects of the oral administration of Bifidobacterium breve strain A1 [MCC1274] (B. breve A1) on tonic-clonic seizure in a pentylenetetrazole (PTZ)-induced kindling mouse (KD mouse) model. We found that the oral administration of B. breve A1 every other day for 15 days significantly reduced the seizure score, which gradually increased with repetitive injections of PTZ in KD mice. The administration of B. breve A1, but not saline, to KD mice significantly increased the level of Akt Ser473 phosphorylation (p-Akt) in the hippocampus; this increase was maintained for a minimum of 24 h after PTZ administration. Treatment of B. breve A1-administered KD mice with the selective inhibitor of integrin-linked kinase (ILK) Cpd22 significantly increased the seizure score and blocked the antiepileptic effect of B. breve A1. Moreover, Cpd22 blocked the B. breve A1-induced increase in hippocampal p-Akt levels. These results suggest that the ILK-induced phosphorylation of Akt Ser473 in the hippocampus might be involved in the antiepileptic effect of B. breve A1.
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Affiliation(s)
- Toshiaki Ishii
- Department of Basic Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan
| | - Motohiro Kaya
- Center for Industry-University Collaboration, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan
| | - Yoshikage Muroi
- Department of Basic Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan
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11
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Hou YJ, Yang XX, He L, Meng HX. Pathological mechanisms of cold and mechanical stress in modulating cancer progression. Hum Cell 2024; 37:593-606. [PMID: 38538930 DOI: 10.1007/s13577-024-01049-y] [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: 11/22/2023] [Accepted: 02/22/2024] [Indexed: 04/15/2024]
Abstract
Environmental temperature and cellular mechanical force are the inherent factors that participate in various biological processes and regulate cancer progress, which have been hot topics worldwide. They occupy a dominant part in the cancer tissues through different approaches. However, extensive investigation regarding pathological mechanisms in the carcinogenic field. After research, we found cold stress via two means to manipulate tumors: neuroscience and mechanically sensitive ion channels (MICHs) such as TRP families to regulate the physiological and pathological activities. Excessive cold stimulation mediated neuroscience acting on every cancer stage through the hypothalamus-pituitary-adrenocorticoid (HPA) to reach the target organs. Comparatively speaking, mechanical force via Piezo of MICHs controls cancer development. The progression of cancer depends on the internal activation of proto-oncogenes and the external tumorigenic factors; the above two means eventually lead to genetic disorders at the molecular level. This review summarizes the interaction of bidirectional communication between them and the tumor. It covers the main processes from cytoplasm to nucleus related to metastasis cascade and tumor immune escape.
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Affiliation(s)
- Yun-Jing Hou
- Harbin Medical University, Harbin, China
- Department of Precision Medicine Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin-Xin Yang
- Harbin Medical University, Harbin, China
- Department of Precision Medicine Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lin He
- Department of Stomatology, Heilongjiang Provincial Hospital, Harbin, China
| | - Hong-Xue Meng
- Harbin Medical University, Harbin, China.
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, China.
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12
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Zhu X, Zhou Y, Yan S, Qian S, Wang Y, Ju E, Zhang C. Herbal Medicine-Inspired Carbon Quantum Dots with Antibiosis and Hemostasis Effects for Promoting Wound Healing. ACS APPLIED MATERIALS & INTERFACES 2024; 16:8527-8537. [PMID: 38329426 DOI: 10.1021/acsami.3c18418] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Bleeding and bacterial infections are crucial factors affecting wound healing. The usage of herbal medicine-derived materials holds great potential for promoting wound healing. However, the uncertain intrinsic effective ingredients and unclear mechanism of action remain great concerns. Herein, inspired by the herbal medicine Ligusticum wallichii, we reported the synthesis of tetramethylpyrazine-derived carbon quantum dots (TMP-CQDs) for promoting wound healing. Of note, the use of TMP as the precursor instead of L. wallichii ensured the repeatability and homogeneity of the obtained products. Furthermore, TMP-CQDs exhibited high antibacterial activity. Mechanically, TMP-CQDs inhibited the DNA repair, biosynthesis, and quorum sensing of the bacteria and induced intracellular reactive oxygen species (ROS). Moreover, TMP-CQDs could accelerate blood coagulation through activating factor VIII and promoting platelet aggregation. Effective wound healing was achieved by using TMP-CQDs in the Staphylococcus aureus-infected mouse skin wound model. This study sheds light on the development of herbal medicine-inspired materials as effective therapeutic drugs.
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Affiliation(s)
- Xiaofei Zhu
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Yu Zhou
- College of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Shihai Yan
- Department of Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Shining Qian
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Yaohui Wang
- Department of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Enguo Ju
- Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Chunbing Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
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13
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Liu R, Shang W, Liu Y, Xie Y, Luan J, Zhang T, Ma Y, Wang Z, Sun Y, Song X, Han F. Inhibition of the ILK-AKT pathway by upregulation of PARVB contributes to the cochlear cell death in Fascin2 gene knockout mice. Cell Death Discov 2024; 10:89. [PMID: 38374196 PMCID: PMC10876960 DOI: 10.1038/s41420-024-01851-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/29/2024] [Accepted: 02/06/2024] [Indexed: 02/21/2024] Open
Abstract
The Fscn2 (Fascin2) gene encodes an actin cross-linking protein that is involved in the formation of hair cell stereocilia and retina structure. Mutations in Fscn2 gene have been linked to hearing impairment and retinal degeneration in humans and mice. To understand the function of the Fscn2 gene, we generated the Fscn2 knockout mice, which showed progressive loss of hearing and hair cells. Our goal of the present study was to investigate the mechanism underlying cochlear cell death in the Fscn2 knockout mice. Microarray analysis revealed upregulation of expression of PARVB, a local adhesion protein, in the inner ears of Fscn2 knockout mice at 8 weeks of age. Further studies showed increased levels of PARVB together with cleaved-Caspase9 and decreased levels of ILK, p-ILK, p-AKT, and Bcl-2 in the inner ears of Fscn2 knockout mice of the same age. Knockdown of Fscn2 in HEI-OCI cells led to decreased cell proliferation ability and migration rate, along with increased levels of PARVB and decreased levels of ILK, p-ILK, p-AKT, Bcl-2 and activated Rac1 and Cdc42. Overexpression of Fscn2 or inhibition of Parvb expression in HEI-OC1 cells promoted cell proliferation and migration, with increased levels of ILK, p-ILK, p-AKT, and Bcl-2. Finally, FSCN2 binds with PPAR-γ to reduce its nuclear translocation in HEI-OC1 cells, and inhibition of PPAR-γ by GW9662 decreased the level of PARVB and increased the levels of p-AKT, p-ILK, and Bcl-2. Our results suggest that FSCN2 negatively regulates PARVB expression by inhibiting the entry of PPAR-γ into the cell nucleus, resulting in inhibition of ILK-AKT related pathways and of cochlear cell survival in Fscn2 knockout mice. Our findings provide new insights and ideas for the prevention and treatment of genetic hearing loss.
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Affiliation(s)
- Rongrong Liu
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China
- Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, PR China
| | - Wenjing Shang
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China
| | - Yingying Liu
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China
| | - Yi Xie
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China
| | - Jun Luan
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China
| | - Ting Zhang
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China
| | - Ying Ma
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China
| | - Zengxian Wang
- Institute of Neurobiology, School of Medicine, Xi'an Siyuan University, 28 Shui An Road, Xi'an, 710038, Shaanxi, PR China
| | - Yan Sun
- Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, PR China.
| | - Xicheng Song
- Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, PR China.
| | - Fengchan Han
- Department of Biochemistry and Molecular Biology, and Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai, 264003, Shandong, PR China.
- Institute of Neurobiology, School of Medicine, Xi'an Siyuan University, 28 Shui An Road, Xi'an, 710038, Shaanxi, PR China.
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14
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Zhang J, Liu F, Guo W, Bi X, Yuan S, Shayiti F, Pan T, Li K, Chen P. Single-cell transcriptome sequencing reveals aberrantly activated inter-tumor cell signaling pathways in the development of clear cell renal cell carcinoma. J Transl Med 2024; 22:37. [PMID: 38191424 PMCID: PMC10775677 DOI: 10.1186/s12967-023-04818-9] [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: 09/28/2023] [Accepted: 12/19/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Aberrant intracellular or intercellular signaling pathways are important mechanisms that contribute to the development and progression of cancer. However, the intercellular communication associated with the development of ccRCC is currently unknown. The purpose of this study was to examine the aberrant tumor cell-to-cell communication signals during the development of ccRCC. METHODS We conducted an analysis on the scRNA-seq data of 6 ccRCC and 6 normal kidney tissues. This analysis included sub clustering, CNV analysis, single-cell trajectory analysis, cell-cell communication analysis, and transcription factor analysis. Moreover, we performed validation tests on clinical samples using multiplex immunofluorescence. RESULTS This study identified eleven aberrantly activated intercellular signaling pathways in tumor clusters from ccRCC samples. Among these, two of the majors signaling molecules, MIF and SPP1, were mainly secreted by a subpopulation of cancer stem cells. This subpopulation demonstrated high expression levels of the cancer stem cell markers POU5F1 and CD44 (POU5F1hiCD44hiE.T), with the transcription factor POU5F1 regulating the expression of SPP1. Further research demonstrated that SPP1 binds to integrin receptors on the surface of target cells and promotes ccRCC development and progression by activating potential signaling mechanisms such as ILK and JAK/STAT. CONCLUSION Aberrantly activated tumor intercellular signaling pathways promote the development and progression of ccRCC. The cancer stem cell subpopulation (POU5F1hiCD44hiE.T) promotes malignant transformation and the development of a malignant phenotype by releasing aberrant signaling molecules and interacting with other tumor cells.
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Affiliation(s)
- Junfeng Zhang
- Department of Urology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China
- Department of Urology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158 Wuyang Avenue, Enshi, 445000, Hubei, China
| | - Fuzhong Liu
- Cancer Institute, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China
| | - Wenjia Guo
- Cancer Institute, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China
| | - Xing Bi
- Department of Urology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China
| | - Shuai Yuan
- Department of Urology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China
| | - Fuerhaiti Shayiti
- Department of Urology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China
| | - Ting Pan
- Department of Urology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China
| | - Kailing Li
- Department of Urology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158 Wuyang Avenue, Enshi, 445000, Hubei, China.
| | - Peng Chen
- Department of Urology, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, China.
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15
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Ahmed AU, Almasabi S, Firestein R, Williams BRG. Integrin-linked kinase expression in myeloid cells promotes colon tumorigenesis. Front Immunol 2023; 14:1270194. [PMID: 38077324 PMCID: PMC10710162 DOI: 10.3389/fimmu.2023.1270194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and treatment options for advanced CRC, which has a low 5-year survival rate, remain limited. Integrin-linked kinase (ILK), a multifunctional, scaffolding, pseudo-kinase regulating many integrin-mediated cellular processes, is highly expressed in many cancers. However, the role of ILK in cancer progression is yet to be fully understood. We have previously uncovered a pro-inflammatory role for myeloid-specific ILK in dextran sodium sulfate (DSS)-induced colitis. To establish a correlation between chronic intestinal inflammation and colorectal cancer (CRC), we investigated the role of myeloid-ILK in mouse models of CRC. When myeloid-ILK deficient mice along with the WT control mice were subjected to colitis-associated and APCmin/+-driven CRC, tumour burden was reduced by myeloid-ILK deficiency in both models. The tumour-promoting phenotype of macrophages, M2 polarization, in vitro was impaired by the ILK deficiency and the number of M2-specific marker CD206-expressing tumour-associated macrophages (TAMs) in vivo were significantly diminished in myeloid-ILK deficient mice. Myeloid-ILK deficient mice showed enhanced tumour infiltration of CD8+ T cells and reduced tumour infiltration of FOXP3+ T cells in colitis-associated and APCmin/+-driven CRC, respectively, with an overall elevated CD8+/FOXP3+ ratio suggesting an anti-tumour immune phenotypes. In patient CRC tissue microarrays we observed elevated ILK+ myeloid (ILK+ CD11b+) cells in tumour sections compared to adjacent normal tissues, suggesting a conserved role for myeloid-ILK in CRC development in both human and animal models. This study identifies myeloid-specific ILK expression as novel driver of CRC, which could be targeted as a potential therapeutic option for advanced disease.
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Affiliation(s)
- Afsar U Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Saleh Almasabi
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Ron Firestein
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Bryan R G Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
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16
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Amano H, Inoue T, Kusano T, Fukaya D, Kosakai W, Okada H. Module 4-Deficient CCN2/Connective Tissue Growth Factor Attenuates the Progression of Renal Fibrosis via Suppression of Focal Adhesion Kinase Phosphorylation in Tubular Epithelial Cells. Mol Cell Biol 2023; 43:515-530. [PMID: 37746701 PMCID: PMC10569360 DOI: 10.1080/10985549.2023.2253130] [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: 09/05/2022] [Accepted: 08/08/2023] [Indexed: 09/26/2023] Open
Abstract
CCN2/connective tissue growth factor (CTGF) potentially serves as a therapeutic target for chronic kidney disease. Here we investigated CCN2 module-4, encoded by Ccn2 exon 5, through the generation of Ccn2 exon 5 knockout mice (Ex5-/- mice). To investigate renal fibrosis pathogenesis, Ex5-/- mice were employed to model unilateral ureteral obstruction (UUO), unilateral ischemic-reperfusion injury (UIRI), and 5/6 nephrectomy. Interstitial fibrosis was significantly attenuated in the Ex5-/- mice in the three models. Furthermore, phosphorylated focal adhesion kinase (FAK) levels in tubular epithelial cells were significantly lower in the kidneys of the UUO- and UIRI-Ex5-/- mice than those of the Ex5+/+ mice. Moreover, CCN2 module 4-mediated renal tubule FAK and promoted fibrosis. These findings indicate that CCN2 module-4-FAK pathway components will serve as therapeutic targets for effectively attenuating renal fibrosis.
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Affiliation(s)
- Hiroaki Amano
- Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Tsutomu Inoue
- Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Takeru Kusano
- General Internal Medicine, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Daichi Fukaya
- Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Wakako Kosakai
- Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Hirokazu Okada
- Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
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17
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Li S, Sampson C, Liu C, Piao HL, Liu HX. Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities. Cell Commun Signal 2023; 21:266. [PMID: 37770930 PMCID: PMC10537162 DOI: 10.1186/s12964-023-01264-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 08/09/2023] [Indexed: 09/30/2023] Open
Abstract
Integrins are transmembrane receptors that possess distinct ligand-binding specificities in the extracellular domain and signaling properties in the cytoplasmic domain. While most integrins have a short cytoplasmic tail, integrin β4 has a long cytoplasmic tail that can indirectly interact with the actin cytoskeleton. Additionally, 'inside-out' signals can induce integrins to adopt a high-affinity extended conformation for their appropriate ligands. These properties enable integrins to transmit bidirectional cellular signals, making it a critical regulator of various biological processes.Integrin expression and function are tightly linked to various aspects of tumor progression, including initiation, angiogenesis, cell motility, invasion, and metastasis. Certain integrins have been shown to drive tumorigenesis or amplify oncogenic signals by interacting with corresponding receptors, while others have marginal or even suppressive effects. Additionally, different α/β subtypes of integrins can exhibit opposite effects. Integrin-mediated signaling pathways including Ras- and Rho-GTPase, TGFβ, Hippo, Wnt, Notch, and sonic hedgehog (Shh) are involved in various stages of tumorigenesis. Therefore, understanding the complex regulatory mechanisms and molecular specificities of integrins are crucial to delaying cancer progression and suppressing tumorigenesis. Furthermore, the development of integrin-based therapeutics for cancer are of great importance.This review provides an overview of integrin-dependent bidirectional signaling mechanisms in cancer that can either support or oppose tumorigenesis by interacting with various signaling pathways. Finally, we focus on the future opportunities for emergent therapeutics based on integrin agonists. Video Abstract.
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Affiliation(s)
- Siyi Li
- Department of Thoracic Surgery, Cancer Research Institute, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Chibuzo Sampson
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Changhao Liu
- Department of Thoracic Surgery, Cancer Research Institute, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China
| | - Hai-Long Piao
- Department of Thoracic Surgery, Cancer Research Institute, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang, 110122, China.
| | - Hong-Xu Liu
- Department of Thoracic Surgery, Cancer Research Institute, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
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18
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Hekmatshoar Y, Karadag Gurel A, Ozkan T, Rahbar Saadat Y, Koc A, Karabay AZ, Bozkurt S, Sunguroglu A. Phenotypic and functional characterization of subpopulation of Imatinib resistant chronic myeloid leukemia cell line. Adv Med Sci 2023; 68:238-248. [PMID: 37421850 DOI: 10.1016/j.advms.2023.06.002] [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: 11/29/2022] [Revised: 03/09/2023] [Accepted: 06/20/2023] [Indexed: 07/10/2023]
Abstract
PURPOSE Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of BCR-ABL protein. Imatinib (IMA) is considered as the first line therapy in management of CML which particularly targets the BCR-ABL tyrosine kinase protein. However, emergence of resistance to IMA hinders its clinical efficiency. Hence, identifying novel targets for therapeutic approaches in CML treatment is of great importance. Here, we characterize a new subpopulation of highly adherent IMA-resistant CML cells that express stemness and adhesion markers compared to naive counterparts. MATERIALS AND METHODS We performed several experimental assays including FISH, flow cytometry, and gene expression assays. Additionally, bioinformatics analysis was performed by normalized web-available microarray data (GSE120932) to revalidate and introduce probable biomarkers. Protein-protein interactions (PPI) network was analyzed by the STRING database employing Cytoscape v3.8.2. RESULTS Our findings demonstrated that constant exposure to 5 μM IMA led to development of the adherent phenotype (K562R-adh). FISH and BCR-ABL expression analysis indicated that K562R-adh cells were derived from the original cells (K562R). In order to determine the role of various genes involved in epithelial-mesenchymal transition (EMT) and stem cell characterization, up/down-regulation of various genes including cancer stem cell (CSC), adhesion and cell surface markers and integrins were observed which was similar to the findings of the GSE120932 dataset. CONCLUSION Treating CML patients with tyrosine kinase inhibitors (TKIs) as well as targeting adhesion molecules deemed to be effective approaches in prevention of IMA resistance emergence which in turn may provide promising effects in the clinical management of CML patients.
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MESH Headings
- Humans
- Imatinib Mesylate/pharmacology
- Imatinib Mesylate/therapeutic use
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Drug Resistance, Neoplasm/genetics
- K562 Cells
- Apoptosis
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/metabolism
- Fusion Proteins, bcr-abl/pharmacology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Phenotype
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Affiliation(s)
- Yalda Hekmatshoar
- Department of Medical Biology, School of Medicine, Altinbas University, Istanbul, Turkey; Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey.
| | - Aynur Karadag Gurel
- Department of Medical Biology, School of Medicine, Usak University, Usak, Turkey.
| | - Tulin Ozkan
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
| | | | - Asli Koc
- Faculty of Pharmacy, Department of Biochemistry, Ankara University, Ankara, Turkey
| | - Arzu Zeynep Karabay
- Faculty of Pharmacy, Department of Biochemistry, Ankara University, Ankara, Turkey
| | - Sureyya Bozkurt
- Department of Medical Biology, School of Medicine, Istinye University, Istanbul, Turkey
| | - Asuman Sunguroglu
- Department of Medical Biology, School of Medicine, Ankara University, Ankara, Turkey
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19
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Tixi W, Maldonado M, Chang YT, Chiu A, Yeung W, Parveen N, Nelson MS, Hart R, Wang S, Hsu WJ, Fueger P, Kopp JL, Huising MO, Dhawan S, Shih HP. Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation. eLife 2023; 12:e90006. [PMID: 37610090 PMCID: PMC10482429 DOI: 10.7554/elife.90006] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 07/12/2023] [Indexed: 08/24/2023] Open
Abstract
Pancreatic islets are three-dimensional cell aggregates consisting of unique cellular composition, cell-to-cell contacts, and interactions with blood vessels. Cell aggregation is essential for islet endocrine function; however, it remains unclear how developing islets establish aggregation. By combining genetic animal models, imaging tools, and gene expression profiling, we demonstrate that islet aggregation is regulated by extracellular matrix signaling and cell-cell adhesion. Islet endocrine cell-specific inactivation of extracellular matrix receptor integrin β1 disrupted blood vessel interactions but promoted cell-cell adhesion and the formation of larger islets. In contrast, ablation of cell-cell adhesion molecule α-catenin promoted blood vessel interactions yet compromised islet clustering. Simultaneous removal of integrin β1 and α-catenin disrupts islet aggregation and the endocrine cell maturation process, demonstrating that establishment of islet aggregates is essential for functional maturation. Our study provides new insights into understanding the fundamental self-organizing mechanism for islet aggregation, architecture, and functional maturation.
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Affiliation(s)
- Wilma Tixi
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
| | - Maricela Maldonado
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
- Department of Biomedical Engineering, College of Engineering, California State University, Long BeachLong BeachUnited States
| | - Ya-Ting Chang
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
| | - Amy Chiu
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
| | - Wilson Yeung
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
| | - Nazia Parveen
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
| | - Michael S Nelson
- Light Microscopy Core, Beckman Research Institute, City of HopeDuarteUnited States
| | - Ryan Hart
- Department of Neurobiology, Physiology and Behavior, University of California, DavisDavisUnited States
| | - Shihao Wang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British ColumbiaVancouverCanada
| | - Wu Jih Hsu
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British ColumbiaVancouverCanada
| | - Patrick Fueger
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
| | - Janel L Kopp
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British ColumbiaVancouverCanada
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, University of California, DavisDavisUnited States
- Department of Physiology and Membrane Biology, School of Medicine, University of California, DavisDavisUnited States
| | - Sangeeta Dhawan
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
| | - Hung Ping Shih
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of HopeDuarteUnited States
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20
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Cao F, Jiang Y, Chang L, Du H, Chang D, Pan C, Huang X, Yu D, Zhang M, Fan Y, Bian X, Li K. High-throughput functional screen identifies YWHAZ as a key regulator of pancreatic cancer metastasis. Cell Death Dis 2023; 14:431. [PMID: 37452033 PMCID: PMC10349114 DOI: 10.1038/s41419-023-05951-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 06/27/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Pancreatic cancer is a leading cause of cancer death due to its early metastasis and limited response to the current therapies. Metastasis is a complicated multistep process, which is determined by complex genetic alterations. Despite the identification of many metastasis-related genes, distinguishing the drivers from numerous passengers and establishing the causality in cancer pathophysiology remains challenging. Here, we established a high-throughput and piggyBac transposon-based genetic screening platform, which enables either reduced or increased expression of chromosomal genes near the incorporation site of the gene search vector cassette that contains a doxycycline-regulated promoter. Using this strategy, we identified YWHAZ as a key regulator of pancreatic cancer metastasis. We demonstrated that functional activation of Ywhaz by the gene search vector led to enhanced metastatic capability in mouse pancreatic cancer cells. The metastasis-promoting role of YWHAZ was further validated in human pancreatic cancer cells. Overexpression of YWHAZ resulted in more aggressive metastatic phenotypes in vitro and a shorter survival rate in vivo by modulating epithelial-to-mesenchymal transition. Hence, our study established a high-throughput screening method to investigate the functional relevance of novel genes and validated YWHAZ as a key regulator of pancreatic cancer metastasis.
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Affiliation(s)
- Fang Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yunpeng Jiang
- Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Chang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Endoscopy Center, Peking University Cancer Hospital & Institute, Beijing, China
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - Hongzhen Du
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - De Chang
- Department of Pulmonary and Critical Care Medicine, 7th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Chunxiao Pan
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - Xiaozheng Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Donglin Yu
- Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Mi Zhang
- Department of Pulmonary and Critical Care Medicine, 7th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yongna Fan
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - Xiaocui Bian
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China.
| | - Kailong Li
- Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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21
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Luo J, Zou H, Guo Y, Tong T, Chen Y, Xiao Y, Pan Y, Li P. The oncogenic roles and clinical implications of YAP/TAZ in breast cancer. Br J Cancer 2023; 128:1611-1624. [PMID: 36759723 PMCID: PMC10133323 DOI: 10.1038/s41416-023-02182-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/16/2023] [Accepted: 01/23/2023] [Indexed: 02/11/2023] Open
Abstract
Breast cancer (BC) is the most commonly diagnosed form of cancer and a leading cause of cancer-related deaths among women worldwide. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are homologous transcriptional coactivators and downstream effectors of Hippo signalling. YAP/TAZ activation has been revealed to play essential roles in multiple events of BC development, including tumour initiation, progression, metastasis, drug resistance and stemness regulations. In this review, we will first give an overview of YAP/TAZ-mediated oncogenesis in BC, and then systematically summarise the oncogenic roles of YAP/TAZ in various BC subtypes, BC stem cells (BCSCs) and tumour microenvironments (TMEs). Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based targeted therapies in BC and the potential future direction.
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Affiliation(s)
- Juan Luo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Hailin Zou
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yibo Guo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Tongyu Tong
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China.,Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yun Chen
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yunjun Xiao
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yihang Pan
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China. .,Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China.
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China. .,Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China.
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22
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Ho CSH, Soh MWT, Tay GWN. The diagnostic utility of miRNA and elucidation of pathological mechanisms in major depressive disorder. Compr Psychiatry 2023; 121:152363. [PMID: 36580691 DOI: 10.1016/j.comppsych.2022.152363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/20/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022] Open
Abstract
AIMS Our study aims to explore how miRNAs can elucidate the molecular mechanisms of major depressive disorder (MDD) by comparing the miRNA levels in the blood serum of patients with depression and healthy individuals. It also explores the potential of miRNAs to differentiate between depressed patients and healthy controls. METHODS 60 healthy controls (n = 45 females) were matched to 60 depressed patients (n = 10 unmedicated) for age (±7), sex, ethnicity, and years of education. Depression severity was measured using the Hamilton Depression Rating Scale, and venous blood was collected using PAXgene Blood RNA tubes for miRNA profiling. To further identify the depression-related biological pathways that are influenced by differentially expressed miRNAs, networks were constructed using QIAGEN Ingenuity Pathway Analysis. Receiver operating characteristic (ROC) analyses were also conducted to examine the discriminative ability of miRNAs to distinguish between depressed and healthy individuals. RESULTS Six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690 and miR-6895-3p) showed to be considerably down-regulated in unmedicated depressed patients relative to healthy controls. miR-542-3p, in particular, also has experimentally verified mRNA targets that are predicted to be associated with MDD. ROC analyses found that a panel combining miR-542-3p, miR-181b-3p and miR-3690 produced an area under the curve value of 0.67 in distinguishing between depressed and healthy individuals. CONCLUSIONS miRNAs - most notably, miR-542-3p, miR-181b-3p and miR-3690 - may be biomarkers with targets that are implicated in the pathophysiology of depression. They could also be used to distinguish between depressed and healthy individuals with reasonable accuracy.
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Affiliation(s)
- Cyrus Su Hui Ho
- Department of Psychological Medicine, National University Health System, Singapore, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Michelle Wei Ting Soh
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Gabrielle Wann Nii Tay
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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23
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He W, Cheng Z, Huo Z, Lin B, Wang X, Sun Y, Yu S, Cao S, Xue J, Liu R, Lv W, Li Y, Hong S, Xiao H. STRA6 Promotes Thyroid Carcinoma Progression via Activation of the ILK/AKT/mTOR Axis in Cells and Female Nude Mice. Endocrinology 2023; 164:6967061. [PMID: 36592123 DOI: 10.1210/endocr/bqac215] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/24/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND Metastasis has emerged to be an important cause for poor prognosis of thyroid carcinoma (TC) and its molecular mechanisms are not fully understood. STRA6 is a multifunctional membrane protein widely expressed in embryonic and adult tissues. The function and mechanism of STRA6 in TC remain elusive. OBJECTIVE We aimed to explore the role of STRA6 in TC progression and provide a therapeutic target for TC. METHODS The expression and clinicopathological relevance of STRA6 were explored in TC. Stable STRA6-knockdown TC cells were established and used to determine the biological function of STRA6 in vitro and in vivo. RNA sequencing and co-immunoprecipitation were performed to unveil the molecular mechanism of STRA6 in TC progression. The potential of STRA6 as a therapeutic target was evaluated by lipid nanoparticles (LNPs) containing siRNA. RESULTS STRA6 was upregulated in TC and correlated with aggressive clinicopathological features, including extrathyroidal extension and lymph node metastasis, which contributed to the poor prognosis of TC. STRA6 facilitated TC progression by enhancing proliferation and metastasis in vitro and in vivo. Mechanistically, STRA6 could interact with integrin-linked kinase (ILK) and subsequently activate the protein kinase B/mechanistic target of rapamycin (AKT/mTOR) signaling pathway. We further unveiled that STRA6 reprogrammed lipid metabolism through SREBP1, which was crucial for the metastasis of TC. Moreover, STRA6 siRNA delivered by LNPs significantly inhibited cell growth in xenograft tumor models. CONCLUSIONS Our study demonstrates the critical roles of STRA6 contributing to TC progression via the ILK/AKT/mTOR axis, which may provide a novel prognostic marker as well as a promising therapeutic target for aggressive TC.
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Affiliation(s)
- Weiman He
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Zhen Cheng
- Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Zijun Huo
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Bo Lin
- Department of Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Xuejie Wang
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Yijia Sun
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Shuang Yu
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Siting Cao
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junyu Xue
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Rengyun Liu
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Weiming Lv
- Department of Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Yanbing Li
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Shubin Hong
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Haipeng Xiao
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
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24
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Sun Y, Wang H, Qu T, Luo J, An P, Ren F, Luo Y, Li Y. mTORC2: a multifaceted regulator of autophagy. Cell Commun Signal 2023; 21:4. [PMID: 36604720 PMCID: PMC9814435 DOI: 10.1186/s12964-022-00859-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/06/2022] [Indexed: 01/06/2023] Open
Abstract
Autophagy is a multi-step catabolic process that delivers cellular components to lysosomes for degradation and recycling. The dysregulation of this precisely controlled process disrupts cellular homeostasis and leads to many pathophysiological conditions. The mechanistic target of rapamycin (mTOR) is a central nutrient sensor that integrates growth signals with anabolism to fulfil biosynthetic and bioenergetic requirements. mTOR nucleates two distinct evolutionarily conserved complexes (mTORC1 and mTORC2). However, only mTORC1 is acutely inhibited by rapamycin. Consequently, mTORC1 is a well characterized regulator of autophagy. While less is known about mTORC2, the availability of acute small molecule inhibitors and multiple genetic models has led to increased understanding about the role of mTORC2 in autophagy. Emerging evidence suggests that the regulation of mTORC2 in autophagy is mainly through its downstream effector proteins, and is variable under different conditions and cellular contexts. Here, we review recent advances that describe a role for mTORC2 in this catabolic process, and propose that mTORC2 could be a potential clinical target for the treatment of autophagy-related diseases. Video abstract.
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Affiliation(s)
- Yanan Sun
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Huihui Wang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, 730070 China
| | - Taiqi Qu
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Junjie Luo
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Peng An
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Fazheng Ren
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Yongting Luo
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Yixuan Li
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
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25
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Papalazarou V, Drew J, Juin A, Spence HJ, Whitelaw J, Nixon C, Salmeron-Sanchez M, Machesky LM. Collagen VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche. J Cell Sci 2022; 135:jcs259978. [PMID: 36546396 PMCID: PMC9845737 DOI: 10.1242/jcs.259978] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 11/19/2022] [Indexed: 12/24/2022] Open
Abstract
Pancreatic cancer is a deadly and highly metastatic disease, although how metastatic lesions establish is not fully understood. A key feature of pancreatic tumours is extensive fibrosis and deposition of extracellular matrix (ECM). While pancreatic cancer cells are programmed by stimuli derived from a stiff ECM, metastasis requires loss of attachment and adaptation to a softer microenvironment at distant sites. Growing evidence suggests that stiff ECM influences pancreatic cancer cell behaviour. Here, we argue that this influence is reversible and that pancreatic cancer cells can be reprogrammed upon sensing soft substrates. Using engineered polyacrylamide hydrogels with tuneable mechanical properties, we show that collagen VI is specifically upregulated in pancreatic cancer cells on soft substrates, due to a lack of integrin engagement. Furthermore, the expression of collagen VI is inversely correlated with mechanosensing and activity of YAP (also known as YAP1), which might be due to a direct or indirect effect on transcription of genes encoding collagen VI. Collagen VI supports migration in vitro and metastasis formation in vivo. Metastatic nodules formed by pancreatic cancer cells lacking Col6a1 display stromal cell-derived collagen VI deposition, suggesting that collagen VI derived from either cancer cells or the stroma is an essential component of the metastatic niche. This article has an associated First Person interview with Vasileios Papalazarou, joint first author of the paper.
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Affiliation(s)
- Vasileios Papalazarou
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
- Centre for the Cellular Microenvironment, University of Glasgow,Glasgow G11 6EW, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK
| | - James Drew
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Amelie Juin
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Heather J. Spence
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Jamie Whitelaw
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
| | | | - Laura M. Machesky
- Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK
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26
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Cao Y, Lin JH, Hammes HP, Zhang C. Cellular phenotypic transitions in diabetic nephropathy: An update. Front Pharmacol 2022; 13:1038073. [PMID: 36408221 PMCID: PMC9666367 DOI: 10.3389/fphar.2022.1038073] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022] Open
Abstract
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes and is the most common cause of end stage renal disease (ESRD). Renal fibrosis is the final pathological change in DN. It is widely believed that cellular phenotypic switching is the cause of renal fibrosis in diabetic nephropathy. Several types of kidney cells undergo activation and differentiation and become reprogrammed to express markers of mesenchymal cells or podocyte-like cells. However, the development of targeted therapy for DN has not yet been identified. Here, we discussed the pathophysiologic changes of DN and delineated the possible origins that contribute to myofibroblasts and podocytes through phenotypic transitions. We also highlight the molecular signaling pathways involved in the phenotypic transition, which would provide valuable information for the activation of phenotypic switching and designing effective therapies for DN.
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Affiliation(s)
- Yiling Cao
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji-Hong Lin
- 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Hans-Peter Hammes
- 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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27
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Liu J, Zhang Y, Zhou Y, Wang QQ, Ding K, Zhao S, Lu P, Liu JL. Cytoophidia coupling adipose architecture and metabolism. Cell Mol Life Sci 2022; 79:534. [PMID: 36180607 PMCID: PMC11802969 DOI: 10.1007/s00018-022-04567-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 01/05/2023]
Abstract
Tissue architecture determines its unique physiology and function. How these properties are intertwined has remained unclear. Here we show that the metabolic enzyme CTP synthase (CTPS) form filamentous structures termed cytoophidia along the adipocyte cortex in Drosophila adipose tissue. Loss of cytoophidia, whether due to reduced CTPS expression or a point mutation that specifically abrogates its polymerization ability, causes impaired adipocyte adhesion and defective adipose tissue architecture. Moreover, CTPS influences integrin distribution and dot-like deposition of type IV collagen (Col IV). Col IV-integrin signaling reciprocally regulates the assembly of cytoophidia in adipocytes. Our results demonstrate that a positive feedback signaling loop containing both cytoophidia and integrin adhesion complex couple tissue architecture and metabolism in Drosophila adipose tissue.
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Affiliation(s)
- Jingnan Liu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Yuanbing Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Youfang Zhou
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qiao-Qi Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Kang Ding
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- iHuman Institute, ShanghaiTech University, Shanghai, China
| | - Suwen Zhao
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- iHuman Institute, ShanghaiTech University, Shanghai, China
| | - Pengfei Lu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Ji-Long Liu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
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28
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Yang W, Wang H, Guo Q, Xu X, Guo T, Sun L. Roles of TRPV4 in Regulating Circulating Angiogenic Cells to Promote Coronary Microvascular Regeneration. J Cardiovasc Transl Res 2022; 16:414-426. [PMID: 36103035 DOI: 10.1007/s12265-022-10305-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022]
Abstract
To clarify the mechanisms underlying TRPV4 regulating angiogenesis by enhancing the activity of CACs, we detected the angiogenesis ability of HUVEC co-cultured with CACs, the effects of ILK on TRPV4 expression and CACs activity, and the impacts of TRPV4 agonist or inhibitor on cardio-protection of AMI rats with or without CAC transplantation. ILK overexpression or TRPV4 agonist promoted the angiogenesis in HUVEC co-cultured with CACs. ILK overexpression or activation upregulated TRPV4 expression in CACs, while TRPV4 agonist stimulation also regulated ILK expression. TRPV4 agonist effectively improved the myocardial function of AMI rats. Moreover, this effect could be strengthened when combined with CAC transplantation, as CAC transplantation dramatically upregulated the expression of ILK and TRPV4 in heart tissues of AMI rats. Thus, the application of TRPV4 agonist may maintain the activity of CACs to promote angiogenesis and microcirculation reconstruction in the area of myocardial infarction and substantially improve the therapeutic effect.
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Affiliation(s)
- Wenhui Yang
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China
| | - Haizhen Wang
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Qiuzhe Guo
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China
| | - Xiaocui Xu
- Kunming Medical University, Kunming, China
| | - Tao Guo
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China.
| | - Lin Sun
- Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, China.
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Kitsugi K, Noritake H, Matsumoto M, Hanaoka T, Umemura M, Yamashita M, Takatori S, Ito J, Ohta K, Chida T, Ulmasov B, Neuschwander-Tetri BA, Suda T, Kawata K. Arg-Gly-Asp-binding integrins activate hepatic stellate cells via the hippo signaling pathway. Cell Signal 2022; 99:110437. [PMID: 35970425 DOI: 10.1016/j.cellsig.2022.110437] [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: 05/22/2022] [Revised: 07/27/2022] [Accepted: 08/09/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND & AIMS Liver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs. METHODS Immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins. RESULTS CWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK. CONCLUSIONS These results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis.
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Affiliation(s)
- Kensuke Kitsugi
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Hidenao Noritake
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
| | - Moe Matsumoto
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tomohiko Hanaoka
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masahiro Umemura
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Maho Yamashita
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shingo Takatori
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Jun Ito
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuyoshi Ohta
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takeshi Chida
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Barbara Ulmasov
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, United States of America
| | - Brent A Neuschwander-Tetri
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, United States of America
| | - Takafumi Suda
- Division of Respiratory Medicine, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuhito Kawata
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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García-Marín J, Rodríguez-Puyol D, Vaquero JJ. Insight into the mechanism of molecular recognition between human Integrin-Linked Kinase and Cpd22 and its implication at atomic level. J Comput Aided Mol Des 2022; 36:575-589. [PMID: 35869378 PMCID: PMC9512720 DOI: 10.1007/s10822-022-00466-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/11/2022] [Indexed: 10/29/2022]
Abstract
AbsractPseudokinases have received increasing attention over the past decade because of their role in different physiological phenomena. Although pseudokinases lack several active-site residues, thereby hindering their catalytic activity, recent discoveries have shown that these proteins can play a role in intracellular signaling thanks to their non-catalytic functions. Integrin-linked kinase (ILK) was discovered more than two decades ago and was subsequently validated as a promising target for neoplastic diseases. Since then, only a few small-molecule inhibitors have been described, with the V-shaped pyrazole Cpd22 being the most interesting and characterized. However, little is known about its detailed mechanism of action at atomic level. In this study, using a combination of computational chemistry methods including PELE calculations, docking, molecular dynamics and experimental surface plasmon resonance, we were able to prove the direct binding of this molecule to ILK, thus providing the basis of its molecular recognition by the protein and the effect over its architecture. Our breakthroughs show that Cpd22 binding stabilizes the ILK domain by binding to the pseudo-active site in a similar way to the ATP, possibly modulating its scaffolding properties as pseudokinase. Moreover, our results explain the experimental observations obtained during Cpd22 development, thus paving the way to the development of new chemical probes and potential drugs.
Graphical abstract
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31
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Riegel K, Vijayarangakannan P, Kechagioglou P, Bogucka K, Rajalingam K. Recent advances in targeting protein kinases and pseudokinases in cancer biology. Front Cell Dev Biol 2022; 10:942500. [PMID: 35938171 PMCID: PMC9354965 DOI: 10.3389/fcell.2022.942500] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022] Open
Abstract
Kinases still remain the most favorable members of the druggable genome, and there are an increasing number of kinase inhibitors approved by the FDA to treat a variety of cancers. Here, we summarize recent developments in targeting kinases and pseudokinases with some examples. Targeting the cell cycle machinery garnered significant clinical success, however, a large section of the kinome remains understudied. We also review recent developments in the understanding of pseudokinases and discuss approaches on how to effectively target in cancer.
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Affiliation(s)
- Kristina Riegel
- Cell Biology Unit, University Medical Center Mainz, JGU-Mainz, Mainz, Germany
| | | | - Petros Kechagioglou
- Cell Biology Unit, University Medical Center Mainz, JGU-Mainz, Mainz, Germany
| | - Katarzyna Bogucka
- Cell Biology Unit, University Medical Center Mainz, JGU-Mainz, Mainz, Germany
| | - Krishnaraj Rajalingam
- Cell Biology Unit, University Medical Center Mainz, JGU-Mainz, Mainz, Germany
- *Correspondence: Krishnaraj Rajalingam,
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32
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The kinase activity of integrin-linked kinase regulates cellular senescence in gastric cancer. Cell Death Dis 2022; 13:577. [PMID: 35778385 PMCID: PMC9249761 DOI: 10.1038/s41419-022-05020-3] [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: 06/10/2021] [Revised: 06/12/2022] [Accepted: 06/13/2022] [Indexed: 01/21/2023]
Abstract
The activity of integrin-linked kinase (ILK) in cancerous cells is often oncogenic and associated with malignant properties, such as uncontrolled cell cycle progression and evasion from senescence. However, the role of ILK in cellular senescence in gastric cancer (GC) has not been previously examined. We generated single-cell clones of ILK knock-out using CRISPR-Cas9 in human GC lines with mesenchymal or epithelial histology. Cells with no residual ILK expression exhibited strong cellular senescence with diminished clathrin-mediated endocytosis, Surprisingly, ILK loss-induced cellular senescence appeared to be independent of its function in integrin signaling. The low dose of CPD22, a small molecule inhibitor of ILK activity-induced senescence in three GC cell lines with different histologies. Furthermore, senescent cells with ILK depletion transfected with N-terminal truncated ILK mutant remaining catalytic domains displayed the reduction of senescent phenotypes. RNA sequencing and cytokine array results revealed the enrichment of multiple pro-inflammatory signaling pathways in GC lines in the absence of ILK. Our study identified the important role and the potential mechanism of ILK in the cellular senescence of cancerous epithelial cells. The inhibition of ILK activity using small molecule compounds could have a pro-senescent effect as a therapeutic option for GC.
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33
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McDonald PC, Dedhar S. New Perspectives on the Role of Integrin-Linked Kinase (ILK) Signaling in Cancer Metastasis. Cancers (Basel) 2022; 14:cancers14133209. [PMID: 35804980 PMCID: PMC9264971 DOI: 10.3390/cancers14133209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Today, the vast majority of deaths from cancer are due to cancer metastasis. Metastasis requires that cancer cells escape from the initial tumor, travel through blood vessels, and form new tumors in distant host tissues. Integrin-linked kinase (ILK) is overexpressed by many types of cancer cells and provides both structural and signaling functions that are important for successful metastasis. Here, we discuss recent findings that show how ILK is involved in promoting physical changes important for cell motility and invasion, and how ILK relays signals to other machinery components during metastasis, including interactions with components of the immune system and communication between cancer cells and normal cells, to affect the process of metastasis. We also discuss the contribution of ILK to therapeutic resistance and examine efforts to target ILK for the treatment of metastatic disease. Abstract Cancer metastasis is a major barrier to the long-term survival of cancer patients. In cancer cells, integrin engagement downstream of cell-extracellular matrix (ECM) interactions results in the recruitment of cytoskeletal and signaling molecules to form multi-protein complexes to promote processes critical for metastasis. One of the major functional components of these complexes is Integrin Linked Kinase (ILK). Here, we discuss recent advances in our understanding of the importance of ILK as a signaling effector in processes linked to tumor progression and metastasis. New mechanistic insights as to the role of ILK in cellular plasticity, epithelial mesenchymal transition (EMT), migration, and invasion, including the impact of ILK on the formation of invadopodia, filopodia-like protrusions (FLPs), and Neutrophil Extracellular Trap (NET)-induced motility are highlighted. Recent findings detailing the contribution of ILK to therapeutic resistance and the importance of ILK as a potentially therapeutically tractable vulnerability in both solid tumors and hematologic malignancies are discussed. Indeed, pharmacologic inhibition of ILK activity using specific small molecule inhibitors is effective in curtailing the contribution of ILK to these processes, potentially offering a novel therapeutic avenue for inhibiting critical steps in the metastatic cascade leading to reduced drug resistance and increased therapeutic efficacy.
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Affiliation(s)
- Paul C. McDonald
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada;
| | - Shoukat Dedhar
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada;
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Correspondence:
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Nikou S, Arbi M, Dimitrakopoulos FID, Kalogeropoulou A, Geramoutsou C, Zolota V, Kalofonos HP, Taraviras S, Lygerou Z, Bravou V. Ras suppressor-1 (RSU1) exerts a tumor suppressive role with prognostic significance in lung adenocarcinoma. Clin Exp Med 2022:10.1007/s10238-022-00847-8. [PMID: 35729367 DOI: 10.1007/s10238-022-00847-8] [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: 12/18/2021] [Accepted: 05/25/2022] [Indexed: 11/03/2022]
Abstract
Ras suppressor-1 (RSU1), originally described as a suppressor of Ras oncogenic transformation, localizes to focal adhesions interacting with the ILK-PINCH-PARVIN (IPP) complex that exerts a well-established oncogenic role in cancer. However, RSU1 implication in lung cancer is currently unknown. Our study aims to address the role of RSU1 in lung adenocarcinoma (LUADC). We here show that RSU1 protein expression by immunohistochemistry is downregulated in LUADC human tissue samples and represents a significant prognostic indicator. In silico analysis of gene chip and RNA seq data validated our findings. Depletion of RSU1 by siRNA in lung cancer cells promotes anchorage-independent cell growth, cell motility and epithelial to mesenchymal transition (EMT). Silencing of RSU1 also alters IPP complex expression in lung cancer cells. The p29 RSU1 truncated isoform is detected in lung cancer cells, and its expression is downregulated upon RSU1 silencing, whereas it is overexpressed upon ILK overexpression. These findings suggest that RSU1 exerts a tumor suppressive role with prognostic significance in LUADC.
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Affiliation(s)
- Sofia Nikou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, 26504, Patras, Greece
| | - Marina Arbi
- Department of General Biology, Medical School, University of Patras, 26504, Patras, Greece
| | - Foteinos-Ioannis D Dimitrakopoulos
- Molecular Oncology Laboratory, Division of Oncology, Department of Medicine, Medical School, University of Patras, 26504, Patras, Greece
| | - Argiro Kalogeropoulou
- Department of Physiology, School of Medicine, University of Patras, 26504, Rio, Patras, Greece
| | - Christina Geramoutsou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, 26504, Patras, Greece
| | - Vasiliki Zolota
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, 26504, Patras, Greece.,Department of Pathology, University Hospital of Patras, 26504, Patras, Greece
| | - Haralabos P Kalofonos
- Molecular Oncology Laboratory, Division of Oncology, Department of Medicine, Medical School, University of Patras, 26504, Patras, Greece.,Division of Oncology, Department of Internal Medicine, University Hospital of Patras, 26504, Rio Patras, Greece
| | - Stavros Taraviras
- Department of Physiology, School of Medicine, University of Patras, 26504, Rio, Patras, Greece
| | - Zoi Lygerou
- Department of General Biology, Medical School, University of Patras, 26504, Patras, Greece
| | - Vasiliki Bravou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, 26504, Patras, Greece.
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35
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Almasabi S, Boyd R, Ahmed AU, Williams BRG. Integrin-Linked Kinase Expression Characterizes the Immunosuppressive Tumor Microenvironment in Colorectal Cancer and Regulates PD-L1 Expression and Immune Cell Cytotoxicity. Front Oncol 2022; 12:836005. [PMID: 35692780 PMCID: PMC9174997 DOI: 10.3389/fonc.2022.836005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. However, a role for ILK in the tumor microenvironment (TME) and immune evasion has not been investigated. Here, we show a correlation of ILK expression with the immunosuppressive TME and cancer prognosis. We also uncover a role for ILK in the regulation of programmed death-ligand 1 (PD-L1) expression and immune cell cytotoxicity. Interrogation of web-based data-mining platforms, showed upregulation of ILK expression in tumors and adjacent-non tumor tissue of colorectal cancer (CRC) associated with poor survival and advanced stages. ILK expression was correlated with cancer-associated fibroblast (CAFs) and immunosuppressive cell infiltration including regulatory T cells (Treg) and M2 macrophages (M2) in addition to their gene markers. ILK expression was also significantly correlated with the expression of different cytokines and chemokines. ILK expression showed pronounced association with different important immune checkpoints including PD-L1. Deletion of the ILK gene in PD-L1 positive CRC cell lines using a doxycycline inducible-CRISPR/Cas9, resulted in suppression of both the basal and IFNγ-induced PD-L1 expression via downregulating NF-κB p65. This subsequently sensitized the CRC cells to NK92 immune cell cytotoxicity. These findings suggest that ILK can be used as a biomarker for prognosis and immune cell infiltration in colon cancer. Moreover, ILK could provide a therapeutic target to prevent immune evasion mediated by the expression of PD-L1.
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Affiliation(s)
- Saleh Almasabi
- Cancer and Innate Immunity, Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia.,Cartherics, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia.,Clinical Laboratory Sciences, Applied Medical Sciences, Najran University, Najran, Saudi Arabia
| | - Richard Boyd
- Cartherics, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia
| | - Afsar U Ahmed
- Cancer and Innate Immunity, Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia
| | - Bryan R G Williams
- Cancer and Innate Immunity, Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC, Australia
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36
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Lampros M, Vlachos N, Voulgaris S, Alexiou GA. The Role of Hsp27 in Chemotherapy Resistance. Biomedicines 2022; 10:897. [PMID: 35453647 PMCID: PMC9028095 DOI: 10.3390/biomedicines10040897] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/05/2022] [Accepted: 04/09/2022] [Indexed: 01/27/2023] Open
Abstract
Heat shock protein (Hsp)-27 is a small-sized, ATP-independent, chaperone molecule that is overexpressed under conditions of cellular stress such as oxidative stress and heat shock, and protects proteins from unfolding, thus facilitating proteostasis and cellular survival. Despite its protective role in normal cell physiology, Hsp27 overexpression in various cancer cell lines is implicated in tumor initiation, progression, and metastasis through various mechanisms, including modulation of the SWH pathway, inhibition of apoptosis, promotion of EMT, adaptation of CSCs in the tumor microenvironment and induction of angiogenesis. Investigation of the role of Hsp27 in the resistance of various cancer cell types against doxorubicin, herceptin/trastuzumab, gemcitabine, 5-FU, temozolomide, and paclitaxel suggested that Hsp27 overexpression promotes cancer cell survival against the above-mentioned chemotherapeutic agents. Conversely, Hsp27 inhibition increased the efficacy of those chemotherapy drugs, both in vitro and in vivo. Although numerous signaling pathways and molecular mechanisms were implicated in that chemotherapy resistance, Hsp27 most commonly contributed to the upregulation of Akt/mTOR signaling cascade and inactivation of p53, thus inhibiting the chemotherapy-mediated induction of apoptosis. Blockage of Hsp27 could enhance the cytotoxic effect of well-established chemotherapeutic drugs, especially in difficult-to-treat cancer types, ultimately improving patients' outcomes.
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Affiliation(s)
| | | | | | - George A. Alexiou
- Department of Neurosurgery, University Hospital of Ioannina, St. Niarhou Avenue, 45500 Ioannina, Greece; (M.L.); (N.V.); (S.V.)
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Kim CH, Kim DE, Kim DH, Min GH, Park JW, Kim YB, Sung CK, Yim H. Mitotic protein kinase-driven crosstalk of machineries for mitosis and metastasis. Exp Mol Med 2022; 54:414-425. [PMID: 35379935 PMCID: PMC9076678 DOI: 10.1038/s12276-022-00750-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence indicates that mitotic protein kinases are involved in metastatic migration as well as tumorigenesis. Protein kinases and cytoskeletal proteins play a role in the efficient release of metastatic cells from a tumor mass in the tumor microenvironment, in addition to playing roles in mitosis. Mitotic protein kinases, including Polo-like kinase 1 (PLK1) and Aurora kinases, have been shown to be involved in metastasis in addition to cell proliferation and tumorigenesis, depending on the phosphorylation status and cellular context. Although the genetic programs underlying mitosis and metastasis are different, the same protein kinases and cytoskeletal proteins can participate in both mitosis and cell migration/invasion, resulting in migratory tumors. Cytoskeletal remodeling supports several cellular events, including cell division, movement, and migration. Thus, understanding the contributions of cytoskeletal proteins to the processes of cell division and metastatic motility is crucial for developing efficient therapeutic tools to treat cancer metastases. Here, we identify mitotic kinases that function in cancer metastasis as well as tumorigenesis. Several mitotic kinases, namely, PLK1, Aurora kinases, Rho-associated protein kinase 1, and integrin-linked kinase, are considered in this review, as an understanding of the shared machineries between mitosis and metastasis could be helpful for developing new strategies to treat cancer. Improving understanding of the mechanisms linking cell division and cancer spread (metastasis) could provide novel strategies for treatment. A group of enzymes involved in cell division (mitosis) are also thought to play critical roles in the spread of cancers. Hyungshin Yim at Hanyang University in Ansan, South Korea, and co-workers in Korea and the USA reviewed the roles of several mitotic enzymes that are connected with metastasis as well as tumorigenesis. They discussed how these enzymes modify cytoskeletal proteins and other substrates during cancer progression. Some regulatory control of cell cytoskeletal structures is required for cancer cells to metastasize. Recent research has uncovered crosstalk between mitotic enzymes and metastatic cytoskeletal molecules in various cancers. Targeting mitotic enzymes and the ways they influence cytoskeletal mechanisms could provide valuable therapeutic strategies for suppressing metastasis.
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Affiliation(s)
- Chang-Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea
| | - Da-Eun Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea
| | - Dae-Hoon Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea
| | - Ga-Hong Min
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea
| | - Jung-Won Park
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea
| | - Yeo-Bin Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea
| | - Chang K Sung
- Department of Biological and Health Sciences, Texas A&M University-Kingsville, Kingsville, TX, 78363, USA
| | - Hyungshin Yim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea.
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38
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Bertolini I, Perego M, Ghosh JC, Kossenkov AV, Altieri DC. NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment. Oncogene 2022; 41:2520-2525. [PMID: 35354906 PMCID: PMC9040905 DOI: 10.1038/s41388-022-02280-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 01/18/2022] [Accepted: 03/16/2022] [Indexed: 02/02/2023]
Abstract
Small extracellular vesicles (sEV) contribute to the crosstalk between tumor cells and stroma, but the underlying signals are elusive. Here, we show that sEV generated by breast cancer cells in hypoxic (sEVHYP), but not normoxic (sEVNORM) conditions activate NFκB in recipient normal mammary epithelial cells. This increases the production and release of inflammatory cytokines, promotes mitochondrial dynamics leading to heightened cell motility and disrupts 3D mammary acini architecture with aberrant cell proliferation, reduced apoptosis and EMT. Mechanistically, Integrin-Linked Kinase packaged in sEVHYP via HIF1α is sufficient to activate NFκB in the normal mammary epithelium, in vivo. Therefore, sEVHYP activation of NFκB drives multiple oncogenic steps of inflammation, mitochondrial dynamics, and mammary gland morphogenesis in a breast cancer microenvironment.
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Affiliation(s)
- Irene Bertolini
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA
| | - Michela Perego
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA
| | - Jagadish C Ghosh
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA
| | - Andrew V Kossenkov
- Bioinformatics Shared Resource, The Wistar Institute, Philadelphia, PA, 19104, USA
- Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA
| | - Dario C Altieri
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
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39
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Lu Z, Yuan S, Ruan L, Tu Z, Liu H. Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial–mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer. Cell Death Dis 2022; 13:304. [PMID: 35379775 PMCID: PMC8980072 DOI: 10.1038/s41419-022-04756-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/02/2022] [Accepted: 03/17/2022] [Indexed: 11/17/2022]
Abstract
Partitioning-defective protein 6 (Par6) family proteins have been demonstrated to be closely associated with the occurrence and development of cancers. It is well accepted that dysregulation of epithelial–mesenchymal transition (EMT) greatly contributes to carcinogenesis and metastases of ovarian cancer. So far, the roles of Par6 in EMT of ovarian cancer are not clear. Functional experiments were carried out to study the roles of PARD6A in EMT of ovarian cancer in vitro and in vivo, and EMT pathways potentially affected by PARD6A expression were screened. We found that PARD6A was significantly highly expressed in tissues of ovarian cancer patients in III-IV stages, poorly differentiated or with lymphatic metastases versus I-II stages, moderately or well differentiated, or without lymphatic metastases, respectively. PARD6A knockdown suppressed EMT of SKOV3 and A2780 cells in vitro and ovarian cancer metastasis in vivo, while overexpression of PARD6A promoted EMT in HO8910 and OVCAR8 cells. It was indicated that PARD6A affected EMT of ovarian cancer cells through SNAIL1 signaling pathway and subsequently modulated the expression of VIMENTIN and E-cadherin, which was further confirmed by knockdown and overexpression of SNAIL1 experiments. PARD6A was also demonstrated to regulate expression of SNAIL1 by modulating integrin β1 and ILK proteins, specifically it was shown that the transcription of SNAIL1 was regulated by ILK in this study. In addition, expression of ILK in ovarian cancer tissues was demonstrated to be correlated with tumor stages and lymphatic metastases clinically. In this study, we identified a novel role of PARD6A as an inducer of cell migration and invasion, which is likely to play an important role in metastasis of ovarian cancer. The molecular pathways of EMT mediated by PARD6A-Integrin β1-ILK-SNAIL1 and finally implemented by E-cadherin and VIMENTIN may provide a novel strategy for drug development for ovarian cancer therapy in the near future.
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ATP allosterically stabilizes integrin-linked kinase for efficient force generation. Proc Natl Acad Sci U S A 2022; 119:e2106098119. [PMID: 35259013 PMCID: PMC8933812 DOI: 10.1073/pnas.2106098119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The pseudokinase integrin-linked kinase (ILK) is a central component of focal adhesions, cytoplasmic multiprotein complexes that integrate and transduce biochemical and mechanical signals from the extracellular environment into the cell and vice versa. However, the precise molecular functions, particularly the mechanosensory properties of ILK and the significance of retained adenosine triphosphate (ATP) binding, are still unclear. Combining molecular-dynamics simulations with cell biology, we establish a role for ATP binding to pseudokinases. We find that ATP promotes the structural stability of ILK, allosterically influences the interaction between ILK and its binding partner parvin at adhesions, and enhances the mechanoresistance of this complex. On the cellular level, ATP binding facilitates efficient traction force buildup, focal adhesion stabilization, and efficient cell migration. Focal adhesions link the actomyosin cytoskeleton to the extracellular matrix regulating cell adhesion, shape, and migration. Adhesions are dynamically assembled and disassembled in response to extrinsic and intrinsic forces, but how the essential adhesion component integrin-linked kinase (ILK) dynamically responds to mechanical force and what role adenosine triphosphate (ATP) bound to this pseudokinase plays remain elusive. Here, we apply force–probe molecular-dynamics simulations of human ILK:α-parvin coupled to traction force microscopy to explore ILK mechanotransducing functions. We identify two key salt-bridge–forming arginines within the allosteric, ATP-dependent force-propagation network of ILK. Disrupting this network by mutation impedes parvin binding, focal adhesion stabilization, force generation, and thus migration. Under tension, ATP shifts the balance from rupture of the complex to protein unfolding, indicating that ATP increases the force threshold required for focal adhesion disassembly. Our study proposes a role of ATP as an obligatory binding partner for structural and mechanical integrity of the pseudokinase ILK, ensuring efficient cellular force generation and migration.
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Gomes KP, Jadli AS, de Almeida LGN, Ballasy NN, Edalat P, Shandilya R, Young D, Belke D, Shearer J, Dufour A, Patel VB. Proteomic Analysis Suggests Altered Mitochondrial Metabolic Profile Associated With Diabetic Cardiomyopathy. Front Cardiovasc Med 2022; 9:791700. [PMID: 35310970 PMCID: PMC8924072 DOI: 10.3389/fcvm.2022.791700] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 01/24/2022] [Indexed: 01/04/2023] Open
Abstract
Diabetic cardiomyopathy (DbCM) occurs independently of cardiovascular diseases or hypertension, leading to heart failure and increased risk for death in diabetic patients. To investigate the molecular mechanisms involved in DbCM, we performed a quantitative proteomic profiling analysis in the left ventricle (LV) of type 2 diabetic mice. Six-month-old C57BL/6J-lepr/lepr (db/db) mice exhibited DbCM associated with diastolic dysfunction and cardiac hypertrophy. Using quantitative shotgun proteomic analysis, we identified 53 differentially expressed proteins in the LVs of db/db mice, majorly associated with the regulation of energy metabolism. The subunits of ATP synthase that form the F1 domain, and Cytochrome c1, a catalytic core subunit of the complex III primarily responsible for electron transfer to Cytochrome c, were upregulated in diabetic LVs. Upregulation of these key proteins may represent an adaptive mechanism by diabetic heart, resulting in increased electron transfer and thereby enhancement of mitochondrial ATP production. Conversely, diabetic LVs also showed a decrease in peptide levels of NADH dehydrogenase 1β subcomplex subunit 11, a subunit of complex I that catalyzes the transfer of electrons to ubiquinone. Moreover, the atypical kinase COQ8A, an essential lipid-soluble electron transporter involved in the biosynthesis of ubiquinone, was also downregulated in diabetic LVs. Our study indicates that despite attempts by hearts from diabetic mice to augment mitochondrial ATP energetics, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production. Preserved basal mitochondrial respiration along with the markedly reduced maximal respiratory capacity in the LVs of db/db mice corroborate the association between altered mitochondrial metabolic profile and cardiac dysfunction in DbCM.
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Affiliation(s)
- Karina P. Gomes
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Anshul S. Jadli
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Luiz G. N. de Almeida
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- McCaig Institute for Bone and Joint Health, Calgary, AB, Canada
| | - Noura N. Ballasy
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Pariya Edalat
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Ruchita Shandilya
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Daniel Young
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- McCaig Institute for Bone and Joint Health, Calgary, AB, Canada
| | - Darrell Belke
- Libin Cardiovascular Institute, Calgary, AB, Canada
- Department of Cardiac Sciences, Cumming School of Medicine, Calgary, AB, Canada
| | - Jane Shearer
- Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Antoine Dufour
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- McCaig Institute for Bone and Joint Health, Calgary, AB, Canada
- Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Vaibhav B. Patel
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada
- Libin Cardiovascular Institute, Calgary, AB, Canada
- *Correspondence: Vaibhav B. Patel ;
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Górska A, Mazur AJ. Integrin-linked kinase (ILK): the known vs. the unknown and perspectives. Cell Mol Life Sci 2022; 79:100. [PMID: 35089438 PMCID: PMC8799556 DOI: 10.1007/s00018-021-04104-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/29/2021] [Accepted: 12/17/2021] [Indexed: 02/08/2023]
Abstract
Integrin-linked kinase (ILK) is a multifunctional molecular actor in cell-matrix interactions, cell adhesion, and anchorage-dependent cell growth. It combines functions of a signal transductor and a scaffold protein through its interaction with integrins, then facilitating further protein recruitment within the ILK-PINCH-Parvin complex. ILK is involved in crucial cellular processes including proliferation, survival, differentiation, migration, invasion, and angiogenesis, which reflects on systemic changes in the kidney, heart, muscle, skin, and vascular system, also during the embryonal development. Dysfunction of ILK underlies the pathogenesis of various diseases, including the pro-oncogenic activity in tumorigenesis. ILK localizes mostly to the cell membrane and remains an important component of focal adhesion. We do know much about ILK but a lot still remains either uncovered or unclear. Although it was initially classified as a serine/threonine-protein kinase, its catalytical activity is now questioned due to structural and functional issues, leaving the exact molecular mechanism of signal transduction by ILK unsolved. While it is known that the three isoforms of ILK vary in length, the presence of crucial domains, and modification sites, most of the research tends to focus on the main isoform of this protein while the issue of functional differences of ILK2 and ILK3 still awaits clarification. The activity of ILK is regulated on the transcriptional, protein, and post-transcriptional levels. The crucial role of phosphorylation and ubiquitylation has been investigated, but the functions of the vast majority of modifications are still unknown. In the light of all those open issues, here we present an extensive literature survey covering a wide spectrum of latest findings as well as a past-to-present view on controversies regarding ILK, finishing with pointing out some open questions to be resolved by further research.
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Affiliation(s)
- Agata Górska
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, ul. Joliot-Curie 14a, 50-383, Wrocław, Poland.
| | - Antonina Joanna Mazur
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, ul. Joliot-Curie 14a, 50-383, Wrocław, Poland.
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Garcia-Marin J, Griera-Merino M, Matamoros-Recio A, de Frutos S, Rodríguez-Puyol M, Alajarín R, Vaquero JJ, Rodríguez-Puyol D. Tripeptides as Integrin-Linked Kinase Modulating Agents Based on a Protein-Protein Interaction with α-Parvin. ACS Med Chem Lett 2021; 12:1656-1662. [PMID: 34790291 PMCID: PMC8591738 DOI: 10.1021/acsmedchemlett.1c00183] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/13/2021] [Indexed: 01/01/2023] Open
Abstract
![]()
Integrin-linked
kinase (ILK) has emerged as a controversial pseudokinase
protein that plays a crucial role in the signaling process initiated
by integrin-mediated signaling. However, ILK also exhibits a scaffolding
protein function inside cells, controlling cytoskeletal dynamics,
and has been related to non-neoplastic diseases such as chronic kidney
disease (CKD). Although this protein always acts as a heterotrimeric
complex bound to PINCH and parvin adaptor proteins, the role of parvin
proteins is currently not well understood. Using in silico approaches
for the design, we have generated and prepared a set of new tripeptides
mimicking an α-parvin segment. These derivatives exhibit activity
in phenotypic assays in an ILK-dependent manner without altering kinase
activity, thus allowing the generation of new chemical probes and
drug candidates with interesting ILK-modulating activities.
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Affiliation(s)
- Javier Garcia-Marin
- Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Alcalá de Henares 28805, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, Madrid 28034, Spain
- Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, Alcalá de Henares 28805, Spain
| | - Mercedes Griera-Merino
- Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares 28805, Spain
- Graphenano Medical Care, S.L, Yecla 30510, Spain
| | - Alejandra Matamoros-Recio
- Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Alcalá de Henares 28805, Spain
| | - Sergio de Frutos
- Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares 28805, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, Madrid 28034, Spain
- Fundación Renal Iñigo Álvarez de Toledo (FRIAT) y Instituto de Salud Carlos III (REDinREN), Madrid 28029, Spain
| | - Manuel Rodríguez-Puyol
- Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares 28805, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, Madrid 28034, Spain
- Fundación Renal Iñigo Álvarez de Toledo (FRIAT) y Instituto de Salud Carlos III (REDinREN), Madrid 28029, Spain
| | - Ramón Alajarín
- Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Alcalá de Henares 28805, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, Madrid 28034, Spain
- Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, Alcalá de Henares 28805, Spain
| | - Juan J. Vaquero
- Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Alcalá de Henares 28805, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, Madrid 28034, Spain
- Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, Alcalá de Henares 28805, Spain
| | - Diego Rodríguez-Puyol
- Fundación de Investigación Biomédica, Unidad de Nefrología del Hospital Príncipe de Asturias y Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares 28805, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, Madrid 28034, Spain
- Fundación Renal Iñigo Álvarez de Toledo (FRIAT) y Instituto de Salud Carlos III (REDinREN), Madrid 28029, Spain
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Zhang Y, Su H, Wudu M, Ren H, Xu Y, Zhang Q, Jiang J, Wang Q, Jiang X, Zhang B, Liu Z, Zou Z, Qiu X. TBC1 domain family member 23 interacts with Ras-related protein Rab-11A to promote poor prognosis of non-small-cell lung cancer via β1-integrin. J Cell Mol Med 2021; 25:8821-8835. [PMID: 34363324 PMCID: PMC8435452 DOI: 10.1111/jcmm.16841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 07/09/2021] [Accepted: 07/26/2021] [Indexed: 11/27/2022] Open
Abstract
Non‐small‐cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer cases. TBC1D23, a member of the TBC/RABGAP family, is widely expressed in human tissues; however, its role in NSCLC is currently unknown. Immunohistochemical analysis was conducted on 173 paraffin‐embedded lung tissue sections from patients with NSCLC from 2014 to 2018 at the First Affiliated Hospital of China Medical University. MTT, colony formation assay, cell cycle assay, scratch assay, transwell assay, Western blotting and real‐time PCR were employed on multiple NSCLC cell lines modified to knock down or overexpress TBC1D23/RAB11A. Immunoprecipitation, immunoprecipitation‐mass spectrometry, immunofluorescence and flow cytometry were performed to explore the interaction between TBC1D23 and RAB11A and TBC1D23 involvement in the interaction between RAB11A and β1 integrin in the para‐nucleus. TBC1D23 was correlated with tumour size, differentiation degree, metastasis, TNM stage and poor prognosis. TBC1D23 was involved in the interaction between RAB11A and β1 integrin in the para‐nucleus, thus activating the β1 integrin/FAK/ERK signalling pathway to promote NSCLC. Furthermore, TBC1D23 promoted NSCLC progression by inducing cell proliferation, migration and invasion. This study indicated the relationship between TBC1D23 expression and the adverse clinicopathological characteristics of patients with NSCLC, suggesting that TBC1D23 may be an important target for NSCLC treatment.
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Affiliation(s)
- Yao Zhang
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Hongbo Su
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Muli Wudu
- Department of Pathology, Basic Medical Sciences, Xinjiang Medical University, Urumqi, China
| | - Hongjiu Ren
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Yitong Xu
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Qingfu Zhang
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Jun Jiang
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Qiongzi Wang
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Xizi Jiang
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Bo Zhang
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
| | - Zongang Liu
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Zifang Zou
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xueshan Qiu
- Department of Pathology, First Affiliated Hospital College and of Basic Medical Sciences China Medical University, Shenyang, China
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Iorio GG, Rovetto MY, Conforti A, Carbone L, Vallone R, Cariati F, Bagnulo F, Di Girolamo R, La Marca A, Alviggi C. Severe Ovarian Hyperstimulation Syndrome in a Woman With Breast Cancer Under Letrozole Triggered With GnRH Agonist: A Case Report and Review of the Literature. FRONTIERS IN REPRODUCTIVE HEALTH 2021; 3:704153. [PMID: 36303992 PMCID: PMC9580822 DOI: 10.3389/frph.2021.704153] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/10/2021] [Indexed: 11/13/2022] Open
Abstract
We report a rare case of ovarian hyperstimulation syndrome (OHSS) in a 28-year-old woman with breast cancer and with a history of polycystic ovary syndrome (PCOS) despite treatment with letrozole and gonadotropin-releasing hormone agonist (GnRH-a) triggering in a GnRH antagonist (GnRH-ant) protocol without the administration of any human chorionic gonadotropin (hCG) for luteal-phase support. The patient, who underwent controlled ovarian syndrome (COS)-oocyte cryopreservation before chemotherapy, required hospitalization. Complete recovery was achieved after treatment with volume expanders, human albumin, and cabergoline. Based on our case and literature review, it is possible to establish that estradiol (E2) modulation with letrozole and GnRH-a triggering does not eliminate the risk of OHSS. Furthermore, it is advisable to postpone GnRH-a depot to minimize the risk of OHSS after the suspension of letrozole, following menstruation or at least 7–8 days after triggering. It would be desirable to identify high-risk patients, also on a genetic basis, in order to avoid delays in oncologic treatments that could strongly impact life expectancy.
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Affiliation(s)
- Giuseppe Gabriele Iorio
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
- *Correspondence: Giuseppe Gabriele Iorio orcid.org/0000-0002-1723-3420
| | - Marika Ylenia Rovetto
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Alessandro Conforti
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Luigi Carbone
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Roberta Vallone
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Federica Cariati
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Francesca Bagnulo
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Raffaella Di Girolamo
- Department of Obstetrics and Gynecology, Center for Fetal Care and High-Risk Pregnancy, University of Chieti, Chieti, Italy
| | - Antonio La Marca
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Alviggi
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Mushtaq U, Bashir M, Nabi S, Khanday FA. Epidermal growth factor receptor and integrins meet redox signaling through P66shc and Rac1. Cytokine 2021; 146:155625. [PMID: 34157521 DOI: 10.1016/j.cyto.2021.155625] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 05/23/2021] [Accepted: 06/08/2021] [Indexed: 12/24/2022]
Abstract
This review examines the concerted role of Epidermal Growth Factor Receptor (EGFR) and integrins in regulating Reactive oxygen species (ROS) production through different signaling pathways. ROS as such are not always deleterious to the cells but they also act as signaling molecules, that regulates numerous indespensible physiological fuctions of life. Many adaptor proteins, particularly Shc and Grb2, are involved in mediating the downstream signaling pathways stimulated by EGFR and integrins. Integrin-induced activation of EGFR and subsequent tyrosine phosphorylation of a class of acceptor sites on EGFR leads to alignment and tyrosine phosphorylation of Shc, PLCγ, the p85 subunit of PI-3 K, and Cbl, followed by activation of the downstream targets Erk and Akt/PKB. Functional interactions between these receptors result in the activation of Rac1 via these adaptor proteins, thereby leading to Reactive Oxygen Species. Both GF and integrin activation can produce oxidants independently, however synergistically there is increased ROS generation, suggesting a mutual cooperation between integrins and GFRs for redox signalling. The ROS produced further promotes feed-forward stimulation of redox signaling events such as MAPK activation and gene expression. This relationship has not been reviewed previously. The literature presented here can have multiple implications, ranging from looking at synergistic effects of integrin and EGFR mediated signaling mechanisms of different proteins to possible therapeutic interventions operated by these two receptors. Furthermore, such mutual redox regulation of crosstalk between EGFR and integrins not only add to the established models of pathological oxidative stress, but also can impart new avenues and opportunities for targeted antioxidant based therapeutics.
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Affiliation(s)
- Umar Mushtaq
- Department of Biotechnology, University of Kashmir, Srinagar, JK 190006, India; Department of Biotechnology, Central University of Kashmir, Ganderbal, JK 191201, India
| | - Muneesa Bashir
- Department of Biotechnology, University of Kashmir, Srinagar, JK 190006, India; Department of Higher Education, Government of Jammu & Kashmir, 190001, India
| | - Sumaiya Nabi
- Department of Biochemistry, University of Kashmir, Srinagar, JK 190006, India
| | - Firdous A Khanday
- Department of Biotechnology, University of Kashmir, Srinagar, JK 190006, India.
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Subhan MA, Yalamarty SSK, Filipczak N, Parveen F, Torchilin VP. Recent Advances in Tumor Targeting via EPR Effect for Cancer Treatment. J Pers Med 2021; 11:571. [PMID: 34207137 PMCID: PMC8234032 DOI: 10.3390/jpm11060571] [Citation(s) in RCA: 262] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer causes the second-highest rate of death world-wide. A major shortcoming inherent in most of anticancer drugs is their lack of tumor selectivity. Nanodrugs for cancer therapy administered intravenously escape renal clearance, are unable to penetrate through tight endothelial junctions of normal blood vessels and remain at a high level in plasma. Over time, the concentration of nanodrugs builds up in tumors due to the EPR effect, reaching several times higher than that of plasma due to the lack of lymphatic drainage. This review will address in detail the progress and prospects of tumor-targeting via EPR effect for cancer therapy.
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, Shah Jalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Satya Siva Kishan Yalamarty
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
| | - Nina Filipczak
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
| | - Farzana Parveen
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
- Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Punjab 63100, Pakistan
| | - Vladimir P. Torchilin
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; (S.S.K.Y.); (N.F.); (F.P.)
- Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
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Evaluation of Real-Time In Vitro Invasive Phenotypes. Methods Mol Biol 2021. [PMID: 33742401 DOI: 10.1007/978-1-0716-1350-4_12] [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: 11/22/2023]
Abstract
The methods described here provide a standardized process for assessing in vitro tumor cell migration and invasion in real time. The kinetic data generated under these standardized conditions are reproducible and characteristic of individual tumor cell lines. The complex kinetic features of the data can be analyzed using parameters modeled after pharmacokinetic data processing. Application of the method to the array of tumor types included in the National Cancer Institute's sixty cell line panel (NCI60) revealed distinct modes of invasion with some tumor cell lines utilizing a mesenchymal mode and generating information-rich kinetic profiles. Other cell lines utilized an amoeboid mode not suitable for detection with this method. The method described will be useful as a guide for tumor cell line selection and as a starting point in designing experiments probing migration and invasion.
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Almasabi S, Ahmed AU, Boyd R, Williams BRG. A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity. Front Genet 2021; 12:638558. [PMID: 34163519 PMCID: PMC8216764 DOI: 10.3389/fgene.2021.638558] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/08/2021] [Indexed: 01/10/2023] Open
Abstract
Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. ILK functions as an adaptor and mediator protein linking the extracellular matrix with downstream signaling pathways. ILK is broadly expressed in many human tissues and cells. It is also overexpressed in many cancers, including colorectal cancer (CRC). Inflammation, as evidenced by inflammatory bowel disease (IBD), is one of the highest risk factors for initiating CRC. This has led to the hypothesis that targeting ILK therapeutically could have potential in CRC, as it regulates different cellular processes associated with CRC development and progression as well as inflammation in the colon. A number of studies have indicated an ILK function in senescence, a cellular process that arrests the cell cycle while maintaining active metabolism and transcription. Senescent cells produce different secretions collectively known as the senescence-associated secretory phenotype (SASP). The SASP secretions influence infiltration of different immune cells, either positively for clearing senescent cells or negatively for promoting tumor growth, reflecting the dual role of senescence in cancer. However, a role for ILK in senescence and immunity in CRC remains to be determined. In this review, we discuss the possible role for ILK in senescence and immunity, paying particular attention to the relevance of ILK in CRC. We also examine how activating Toll-like receptors (TLRs) and their agonists in CRC could trigger immune responses against cancer, as a combination therapy with ILK inhibition.
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Affiliation(s)
- Saleh Almasabi
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Cartherics, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Clinical Laboratory Sciences, Applied Medical Sciences, Najran University, Najran, Saudi Arabia.,Department of Molecular and Translational Sciences, Faculty of Medicine Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Afsar U Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Richard Boyd
- Cartherics, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Bryan R G Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
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Integrin-Linked-Kinase Overexpression Is Implicated in Mechanisms of Genomic Instability in Human Colorectal Cancer. Dig Dis Sci 2021; 66:1510-1523. [PMID: 32495257 DOI: 10.1007/s10620-020-06364-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 05/21/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Genomic instability is a hallmark of cancer cells contributing to tumor development and progression. Integrin-linked kinase (ILK) is a focal adhesion protein with well-established role in carcinogenesis. We have previously shown that ILK overexpression is critically implicated in human colorectal cancer (CRC) progression. In light of the recent findings that ILK regulates centrosomes and mitotic spindle formation, we aimed to determine its implication in mechanisms of genomic instability in human CRC. METHODS Association of ILK expression with markers of genomic instability (micronuclei formation, nucleus size, and intensity) was investigated in diploid human colon cancer cells HCT116 upon ectopic ILK overexpression, by immunofluorescence and in human CRC samples by Feulgen staining. We also evaluated the role of ILK in mitotic spindle formation, by immunofluorescence, in HCT116 cells upon inhibition and overexpression of ILK. Finally, we evaluated association of ILK overexpression with markers of DNA damage (p-H2AX, p-ATM/ATR) in human CRC tissue samples by immunohistochemistry and in ILK-overexpressing cells by immunofluorescence. RESULTS We showed that ILK overexpression is associated with genomic instability markers in human colon cancer cells and tissues samples. Aberrant mitotic spindles were observed in cells treated with specific ILK inhibitor (QLT0267), while ILK-overexpressing cells failed to undergo nocodazole-induced mitotic arrest. ILK overexpression was also associated with markers of DNA damage in HCT116 cells and human CRC tissue samples. CONCLUSIONS The above findings indicate that overexpression of ILK is implicated in mechanisms of genomic instability in CRC suggesting a novel role of this protein in cancer.
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