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Asare O, Shim L, Lee CJ, Delgado J, Quailes N, Zavala K, Park J, Hafeez BB, Cho YY, Chauhan SC, Kim DJ. Loss of TC-PTP in keratinocytes leads to increased UVB-induced autophagy. Cell Death Discov 2025; 11:80. [PMID: 40021617 PMCID: PMC11871011 DOI: 10.1038/s41420-025-02353-8] [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: 10/31/2024] [Revised: 01/28/2025] [Accepted: 02/12/2025] [Indexed: 03/03/2025] Open
Abstract
Ultraviolet B (UVB) radiation can distort cellular homeostasis and predispose the skin to carcinogenesis. Amongst the deteriorating effects of the sun's UVB radiation on cellular homeostasis is the formation of DNA photoproducts. These photoproducts can cause significant changes in the structure and conformation of DNA, inducing gene mutations which may accumulate to trigger the formation of skin cancer. Photoproducts are typically repaired by nucleotide excision repair. Notwithstanding, when the repair mechanism fails, apoptosis ensues to prevent the accumulation of mutations and to restore cellular homeostasis. This present study reports that T-cell protein tyrosine phosphatase (TC-PTP) can increase UVB-induced apoptosis by inhibiting autophagy-mediated cell survival of damaged keratinocytes. TC-PTP deficiency in 3PC mouse keratinocytes led to the formation of autophagic vacuoles and increased expression of LC3-II. We established human TC-PTP-deficient (TC-PTP/KO) HaCaT cells using the CRISPR/Cas9 system. TC-PTP/KO HaCaT cells exhibited increased cell survival upon UVB exposure, which was accompanied by increased expression of LC3-II and decreased expression of p62 compared to control cells. Pretreatment of TC-PTP/KO HaCaT cells with early-phase autophagy inhibitor, 3-methyladenine significantly decreased the expression of LC3-II and reduced cell survival in response to UVB irradiation in comparison with untreated TC-PTP/KO cells. Pretreatment of TC-PTP/KO HaCaT cells with late-phase inhibitor, chloroquine also significantly reduced cell viability with increased accumulation of LC3-II after UVB irradiation compared to untreated counterpart cells. While UVB significantly increased apoptosis in the engineered (Mock) cells, this was not observed in similarly treated TC-PTP/KO HaCaT cells. However, chloroquine treatment increased apoptosis in TC-PTP/KO HaCaT cells. Examination of human squamous cell carcinomas (SCCs) revealed that TC-PTP expression was inversely correlated with LC3 expression. Our findings suggest that TC-PTP negatively regulates autophagy-mediated survival of damaged cells following UVB exposure, which can contribute to remove damaged keratinocytes via apoptosis.
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Affiliation(s)
- Obed Asare
- Department of Medicine and Oncology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- Graduate Program in Biochemistry and Molecular Biology, University of Texas Rio Grande Valley, Edinburg, TX, USA
- Graduate Program in Cancer Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lindsey Shim
- Department of Medicine and Oncology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- Graduate Program in Biochemistry and Molecular Biology, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Cheol-Jung Lee
- Department of Medicine and Oncology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- Biopharmaceutical Research Center, Ochang Institute of Biological and Environmental Science, Korea Basic Science Institute, Cheongju-si, 28119, Republic of Korea
| | - Jose Delgado
- School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Natasha Quailes
- School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Klarissa Zavala
- Department of Health & Biomedical Sciences, College of Health Professions, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Junsoo Park
- Division of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
| | - Bilal Bin Hafeez
- Department of Medicine and Oncology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- Graduate Program in Biochemistry and Molecular Biology, University of Texas Rio Grande Valley, Edinburg, TX, USA
- South Texas Center for Excellence in Cancer Research, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Yong-Yeon Cho
- College of Pharmacy, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
- BK21-4TH, and RCD Control Material Research Institute, College of Pharmacy, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea
| | - Subhash C Chauhan
- Department of Medicine and Oncology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- Graduate Program in Biochemistry and Molecular Biology, University of Texas Rio Grande Valley, Edinburg, TX, USA
- South Texas Center for Excellence in Cancer Research, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Dae Joon Kim
- Department of Medicine and Oncology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA.
- Graduate Program in Biochemistry and Molecular Biology, University of Texas Rio Grande Valley, Edinburg, TX, USA.
- South Texas Center for Excellence in Cancer Research, University of Texas Rio Grande Valley, McAllen, TX, USA.
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Huang Q, Hu L, Chen H, Yang B, Sun X, Wang M. A Medicinal Chemistry Perspective on Protein Tyrosine Phosphatase Nonreceptor Type 2 in Tumor Immunology. J Med Chem 2025; 68:3995-4021. [PMID: 39936476 DOI: 10.1021/acs.jmedchem.4c01802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025]
Abstract
PTPN2 (protein tyrosine phosphatase nonreceptor type 2) is an important member of the protein tyrosine phosphatase (PTP) family. It plays a crucial role in dephosphorylating tyrosine-phosphorylated proteins and modulating critical signaling pathways associated with T-cell receptors, IL-2, IFNγ, and various cytokines. In recent years, the PTPN2's biological role has been clarified, particularly since its association with tumor immunology was gradually revealed in 2017, making it a star target for cancer immunotherapy. The dual inhibitor AC484, which targets both PTPN2 and PTP1B, is currently undergoing phase I clinical trials. This advancement has attracted great interest from researchers to develop new drugs based on its unique structure. This review outlines the structural modification processes of PTPN2-targeted agents, focusing primarily on inhibitors and degraders. Finally, this review endeavors to provide a comprehensive perspective on the evolving field of PTPN2-targeted drug discovery for tumor immunotherapy, offering valuable insights for future drug development.
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Affiliation(s)
- Qi Huang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
- School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
| | - Linghao Hu
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
| | - Haowen Chen
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 Guangdong China
| | - Bingjie Yang
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xun Sun
- School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
- The Institutes of Integrative Medicine of Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Mingliang Wang
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 Guangdong China
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
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3
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Gunizi OC, Elpek GO. Protein tyrosine phosphatase nonreceptor 2: A New biomarker for digestive tract cancers. World J Gastrointest Oncol 2025; 17:100546. [PMID: 39958541 PMCID: PMC11756013 DOI: 10.4251/wjgo.v17.i2.100546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/02/2024] [Accepted: 11/20/2024] [Indexed: 01/18/2025] Open
Abstract
In this editorial, the roles of protein tyrosine phosphatase nonreceptor 2 (PTPN2) in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal (GI) cancers are presented with respect to the article by Li et al published in ninth issue of the World Journal of Gastrointestinal Oncology. PTPN2 is a member of the protein tyrosine phosphatase family of signaling proteins that play crucial roles in the regulation of inflammation and immunity. Accordingly, early findings highlighted the contribution of PTPN2 to the pathogenesis of inflammatory and autoimmune disorders related to its dysfunction. On the other hand, recent studies have indicated that PTPN2 has many different roles in different cancer types, which is associated with the complexity of its regulatory network. PTPN2 dephosphorylates and inactivates EGFR, SRC family kinases, JAK1 and JAK3, and STAT1, STAT3, and STAT5 in cell type- and context-dependent manners, which indicates that PTPN2 can perform either prooncogenic or anti-oncogenic functions depending on the tumor subtype. While PTPN2 has been suggested as a potential therapeutic target in cancer treatment, to the best of ourknowledge, no clear treatment protocol has referred to PTPN2. Although there are only few studies that investigated PTPN2 expression in the GI system cancers, which is a potential limitation, the association of this protein with tumor behavior and the influence of PTPN2 on many therapy-related signaling pathways emphasize that PTPN2 could serve as a new molecular biomarker to predict tumor behavior and as a target for therapeutic intervention against GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic potential of PTPN2 in GI tumors, especially in tumors resistant to therapy.
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Affiliation(s)
- Ozlem Ceren Gunizi
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
| | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
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Ma Z, Zhou F, Jin H, Wu X. Crosstalk between CXCL12/CXCR4/ACKR3 and the STAT3 Pathway. Cells 2024; 13:1027. [PMID: 38920657 PMCID: PMC11201928 DOI: 10.3390/cells13121027] [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: 04/25/2024] [Revised: 06/09/2024] [Accepted: 06/10/2024] [Indexed: 06/27/2024] Open
Abstract
The reciprocal modulation between the CXCL12/CXCR4/ACKR3 axis and the STAT3 signaling pathway plays a crucial role in the progression of various diseases and neoplasms. Activation of the CXCL12/CXCR4/ACKR3 axis triggers the STAT3 pathway through multiple mechanisms, while the STAT3 pathway also regulates the expression of CXCL12. This review offers a thorough and systematic analysis of the reciprocal regulatory mechanisms between the CXCL12/CXCR4/ACKR3 signaling axis and the STAT3 signaling pathway in the context of diseases, particularly tumors. It explores the potential clinical applications in tumor treatment, highlighting possible therapeutic targets and novel strategies for targeted tumor therapy.
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Affiliation(s)
| | | | | | - Xiaoming Wu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming 650500, China; (Z.M.); (F.Z.); (H.J.)
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Prutsch N, He S, Berezovskaya A, Durbin AD, Dharia NV, Maher KA, Matthews JD, Hare L, Turner SD, Stegmaier K, Kenner L, Merkel O, Look AT, Abraham BJ, Zimmerman MW. STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma. Cell Rep Med 2024; 5:101472. [PMID: 38508140 PMCID: PMC10983107 DOI: 10.1016/j.xcrm.2024.101472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 12/01/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024]
Abstract
Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.
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Affiliation(s)
- Nicole Prutsch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA
| | - Shuning He
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA
| | - Alla Berezovskaya
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA
| | - Adam D Durbin
- Division of Molecular Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Neekesh V Dharia
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02141, USA
| | - Kelsey A Maher
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jamie D Matthews
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Lucy Hare
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Department of Pediatric Oncology and Hematology, Addenbrooke's Hospital, Cambridge, UK
| | - Suzanne D Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Kimberly Stegmaier
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02141, USA
| | - Lukas Kenner
- Department of Pathology, Unit of Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria
| | - Olaf Merkel
- Department of Pathology, Unit of Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria
| | - A Thomas Look
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
| | - Brian J Abraham
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Mark W Zimmerman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
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Liu S, Liu F, Zhang Z, Zhuang Z, Chen Y. PTPN2 inhibits the proliferation of psoriatic keratinocytes by dephosphorylation of STAT3. Cell Biochem Funct 2024; 42:e3947. [PMID: 38379221 DOI: 10.1002/cbf.3947] [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: 08/21/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 02/22/2024]
Abstract
Psoriasis is a recurrent and protracted disease that severely impacts the patient's physical and mental health. Thus, there is an urgent need to explore its pathogenesis to identify therapeutic targets. The expression level of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) was analyzed by immunohistochemistry techniques in psoriatic tissues and imiquimod-induced psoriatic mouse models. PTPN2 and signal transducer and activator of transcription 3 (STAT3) were overexpressed or silenced in human keratinocytes or an interleukin (IL)-6-induced psoriasis HaCaT cell model using overexpression plasmid transfection or small interfering RNA technology in vitro, and the effects of PTPN2 on STAT3, HaCaT cell function, and autophagy levels were investigated using reverse transcription-quantitative polymerase chain reaction, Western blot, Cell Counting Kit 8, 5-ethynyl-20-deoxyuridine, flow cytometry, and transmission electron microscopy. PTPN2 expression was found to be significantly downregulated in psoriatic tissues. Then, the in vitro antipsoriatic properties of PTPN2 were investigated in an IL-6-induced psoriasis-like cell model, and the results demonstrated that inhibition of keratinocyte proliferation by PTPN2 may be associated with elevated STAT3 dephosphorylation and autophagy levels. These findings provide novel insights into the mechanisms of autophagy in psoriatic keratinocytes and may be essential for developing new therapeutic strategies to improve inflammatory homeostasis in psoriatic patients.
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Affiliation(s)
- Shougang Liu
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Fanghua Liu
- Department of Dermatology, Guangdong Medical University, Zhanjiang, Guangdong, People's Republic of China
- Department of Dermatology, Ganzhou Municipal Hospital, Ganzhou, Jiangxi, People's Republic of China
| | - Zeqiao Zhang
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Zhe Zhuang
- Department of Dermatology, Guangdong Medical University, Zhanjiang, Guangdong, People's Republic of China
| | - Yongfeng Chen
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong, People's Republic of China
- Department of Dermatology, Guangdong Medical University, Zhanjiang, Guangdong, People's Republic of China
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Salmond RJ. Targeting Protein Tyrosine Phosphatases to Improve Cancer Immunotherapies. Cells 2024; 13:231. [PMID: 38334623 PMCID: PMC10854786 DOI: 10.3390/cells13030231] [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: 12/21/2023] [Revised: 01/17/2024] [Accepted: 01/23/2024] [Indexed: 02/10/2024] Open
Abstract
Advances in immunotherapy have brought significant therapeutic benefits to many cancer patients. Nonetheless, many cancer types are refractory to current immunotherapeutic approaches, meaning that further targets are required to increase the number of patients who benefit from these technologies. Protein tyrosine phosphatases (PTPs) have long been recognised to play a vital role in the regulation of cancer cell biology and the immune response. In this review, we summarize the evidence for both the pro-tumorigenic and tumour-suppressor function of non-receptor PTPs in cancer cells and discuss recent data showing that several of these enzymes act as intracellular immune checkpoints that suppress effective tumour immunity. We highlight new data showing that the deletion of inhibitory PTPs is a rational approach to improve the outcomes of adoptive T cell-based cancer immunotherapies and describe recent progress in the development of PTP inhibitors as anti-cancer drugs.
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Affiliation(s)
- Robert J Salmond
- Leeds Institute of Medical Research at St. James's, School of Medicine, University of Leeds, Leeds LS9 7TF, UK
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Sudholz H, Delconte RB, Huntington ND. Interleukin-15 cytokine checkpoints in natural killer cell anti-tumor immunity. Curr Opin Immunol 2023; 84:102364. [PMID: 37451129 DOI: 10.1016/j.coi.2023.102364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/08/2023] [Accepted: 06/09/2023] [Indexed: 07/18/2023]
Abstract
Over recent years, the use of immune checkpoint inhibitors (ICI) has progressed to first and second-line treatments in several cancer types, transforming patient outcomes. While these treatments target T cell checkpoints, such as PD-1, LAG3 and CTLA-4, their efficacy can be compromised through adaptive resistance whereby tumors acquire mutations in genes regulating neoantigen presentation by MHC-I [93]. ICI-responsive tumor types such as advanced metastatic melanoma typically have a high mutational burden and immune infiltration; however, most patients still do not benefit from ICI monotherapy for a number of reasons [94]. This highlights the need for novel immunotherapy strategies that evoke the immune control of tumor cells with low neoantigen/MHC-I expression, overcome immune suppressive tumor microenvironments and promote tumor inflammation. In this regard, targeting natural killer (NK) cells may offer a solution to some of these bottlenecks.
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Affiliation(s)
- Harrison Sudholz
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Rebecca B Delconte
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA
| | - Nicholas D Huntington
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; oNKo-Innate Pty Ltd, Moonee Ponds, Victoria 3039, Australia.
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Li YJ, Zhang C, Martincuks A, Herrmann A, Yu H. STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer 2023; 23:115-134. [PMID: 36596870 DOI: 10.1038/s41568-022-00537-3] [Citation(s) in RCA: 93] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 01/04/2023]
Abstract
Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.
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Affiliation(s)
- Yi-Jia Li
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Chunyan Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Antons Martincuks
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Andreas Herrmann
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
- Sorrento Therapeutics, San Diego, CA, USA
| | - Hua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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Tang X, Sui X, Liu Y. Immune checkpoint PTPN2 predicts prognosis and immunotherapy response in human cancers. Heliyon 2023; 9:e12873. [PMID: 36685446 PMCID: PMC9852697 DOI: 10.1016/j.heliyon.2023.e12873] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/04/2023] [Accepted: 01/05/2023] [Indexed: 01/09/2023] Open
Abstract
Background PTPN2, a member of the non-receptor protein tyrosine phosphatases family, holds a crucial role in tumorigenesis and cancer immunotherapy. However, most studies on the role of PTPN2 in cancer are limited to specific cancer types. Therefore, this study aimed to investigate the prognostic significance of PTPN2 in human cancers and its function in the tumor microenvironment. Methods To shed light on this matter, we investigated the expression level, prognostic value, genomic alterations, molecular function, immune function, and immunotherapeutic predictive ability of PTPN2 in human cancers using the TCGA, GTEx, CGGA, GEO, cBioPortal, STRING, TISCH, TIMER2.0, ESTIMATE, and TIDE databases. Furthermore, the CCK-8 assay was utilized to detect the effect of PTPN2 on cell proliferation. Cell immunofluorescence analysis was performed to probe the cellular localization of PTPN2. Western blot was applied to examine the molecular targets downstream of PTPN2. Finally, a Nomogram model was constructed using the TCGA-LGG cohort and evaluated with calibration curves and time-dependent ROCs. Results PTPN2 was highly expressed in most cancers and was linked to poor prognosis in ACC, GBM, LGG, KICH, and PAAD, while the opposite was true in OV, SKCM, and THYM. PTPN2 knockdown promoted the proliferation of melanoma cells, while significantly inhibiting proliferation in colon cancer and glioblastoma cells. In addition, TC-PTP, encoded by the PTPN2 gene, was primarily localized in the nucleus and cytoplasm and could negatively regulate the JAK/STAT and MEK/ERK pathways. Strikingly, PTPN2 knockdown significantly enhanced the abundance of PD-L1. PTPN2 was abundantly expressed in Mono/Macro cells and positively correlated with multiple immune infiltrating cells, especially CD8+ T cells. Notably, DLBC, LAML, OV, and TGCT patients in the PTPN2-high group responded better to immunotherapy, while the opposite was true in ESCA, KIRC, KIRP, LIHC, and THCA. Finally, the construction of a Nomogram model on LGG exhibited a high prediction accuracy. Conclusion Immune checkpoint PTPN2 is a powerful biomarker for predicting prognosis and the efficacy of immunotherapy in cancers. Mechanistically, PTPN2 negatively regulates the JAK/STAT and MEK/ERK pathways and the abundance of PD-L1.
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Affiliation(s)
- Xiaolong Tang
- Department of Clinical Laboratory Diagnostics, Binzhou Medical University, Binzhou, Shandong 256603, China
| | - Xue Sui
- Department of Clinical Laboratory Diagnostics, Binzhou Medical University, Binzhou, Shandong 256603, China
| | - Yongshuo Liu
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China,Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China,Corresponding author. Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China.
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Nguyen Huu T, Park J, Zhang Y, Duong Thanh H, Park I, Choi JM, Yoon HJ, Park SC, Woo HA, Lee SR. The Role of Oxidative Inactivation of Phosphatase PTEN and TCPTP in Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12010120. [PMID: 36670982 PMCID: PMC9854873 DOI: 10.3390/antiox12010120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent worldwide. Despite the different etiologies, their spectra and histological feature are similar, from simple steatosis to more advanced stages such as steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Studies including peroxiredoxin knockout models revealed that oxidative stress is crucial in these diseases, which present as consequences of redox imbalance. Protein tyrosine phosphatases (PTPs) are a superfamily of enzymes that are major targets of reactive oxygen species (ROS) because of an oxidation-susceptible nucleophilic cysteine in their active site. Herein, we review the oxidative inactivation of two tumor suppressor PTPs, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and T-cell protein tyrosine phosphatase (TCPTP), and their contribution to the pathogenicity of ALD and NAFLD, respectively. This review might provide a better understanding of the pathogenic mechanisms of these diseases and help develop new therapeutic strategies to treat fatty liver disease.
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Affiliation(s)
- Thang Nguyen Huu
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
| | - Jiyoung Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Ying Zhang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Hien Duong Thanh
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
- Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Iha Park
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Jin Myung Choi
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Hyun Joong Yoon
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Sang Chul Park
- The Future Life and Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju 61469, Republic of Korea
| | - Hyun Ae Woo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Seung-Rock Lee
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Correspondence: ; Tel.: +82-61-379-2775; Fax: +82-61-379-2782
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12
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Zhu Z, Tang R, Huff S, Kummetha IR, Wang L, Li N, Rana TM. Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy. CANCER RESEARCH COMMUNICATIONS 2023; 3:119-129. [PMID: 36968224 PMCID: PMC10035454 DOI: 10.1158/2767-9764.crc-21-0186] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 08/23/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022]
Abstract
Although immune checkpoint inhibitors targeting T-cell immunoregulatory proteins have revolutionized cancer treatment, they are effective only in a limited number of patients, and new strategies are needed to enhance tumor responses to immunotherapies. Deletion of protein tyrosine phosphatase non-receptor type 2 (Ptpn2), a regulator of growth factor and cytokine signaling pathways, has been shown to sensitize murine B16F10 melanoma cells to IFNγ and anti-PD-1 immunotherapy. Here, we investigated the potential therapeutic utility of small-molecule PTPN2 inhibitors. Ten inhibitors were synthesized on the basis of in silico modeling and structure-based design and functionally tested in vitro and in vivo. We show that the inhibitors had little effect on B16F10 cells alone, but effectively sensitized the tumor cells to IFNγ treatment in vitro and to anti-PD-1 therapy in vivo. Under both conditions, Ptpn2 inhibitor cotreatment suppressed B16F10 cell growth and enhanced Stat1 phosphorylation and expression of IFNγ response genes. In vivo, PTPN2 inhibitor cotreatment significantly reduced melanoma and colorectal tumor growth and enhanced mouse survival compared with anti-PD-1 treatment alone, and this was accompanied by increased tumor infiltration by granzyme B+ CD8+ T cells. Similar results were obtained with representative murine and human colon cancer and lung cancer cell lines. Collectively, these results demonstrate that small-molecule inhibitors of PTPN2 may have clinical utility as sensitizing agents for immunotherapy-resistant cancers. Significance To enhance the effectiveness of immunotherapies in resistant or nonresponsive cancers, it is important to develop inhibitors of enzymes that negatively influence the outcome of treatments. We have designed and evaluated small-molecule inhibitors of PTPN2 demonstrating that these compounds may have clinical utility as sensitizing agents for immunotherapy-resistant cancers.
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Affiliation(s)
- Zhouting Zhu
- Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California
| | - Rachel Tang
- Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California
| | - Sarah Huff
- Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California
| | - Indrasena Reddy Kummetha
- Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California
| | - Lingling Wang
- Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California
| | - Na Li
- Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California
| | - Tariq M. Rana
- Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California
- San Diego Center for Precision Immunotherapy, Moores Cancer Center, University of California San Diego, La Jolla, California
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13
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Bhattacharjee D, Kaveti S, Jain N. APC/C CDH1 ubiquitinates STAT3 in mitosis. Int J Biochem Cell Biol 2023; 154:106333. [PMID: 36400381 DOI: 10.1016/j.biocel.2022.106333] [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: 06/30/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022]
Abstract
STAT3, an oncogene drives tumor growth and is associated with poor prognosis. However, small molecule-based STAT3 inhibitors were unsuccessful in clinics. Recently, STAT3 degraders that ubiquitinate STAT3 were found to elicit long-lasting anti-tumor responses. Thus, triggering STAT3 ubiquitination in cancers is a better strategy than STAT3 inhibition. However, not much is known about the identity of E3-ligases that ubiquitinate STAT3 in cancers. Therefore, to design better therapies to degrade STAT3, we sought to identify E3-ligases that ubiquitinate STAT3 in cancer cells. To answer this question, we determined the cell cycle-dependent ubiquitination of STAT3 in HEK293T cells and examined the link between STAT3 dephosphorylation and ubiquitination. We found that STAT3 is more strongly ubiquitinated in mitosis than in other phases of the cell cycle. We observed that APC/C CDH1 binds and ubiquitinates STAT3 in mitosis. Further, we also found that inhibiting phosphatases decreases STAT3 ubiquitination. We conclude that APC/C CDH1 ubiquitinates STAT3 in mitosis. We suggest that mitosis can be a potential therapeutic window for treating STAT3-activated cancers.
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Affiliation(s)
- Debanjan Bhattacharjee
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Sector 19, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Sreeram Kaveti
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Sector 19, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Nishant Jain
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Sector 19, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India.
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14
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Shi S, Xu D, Gu S, Xu N, Xu P, Cao J, Feng XH. Protein tyrosine phosphatase PTPN2 regulates TGF-β signaling through Smad4 dephosphorylation. Am J Cancer Res 2022; 12:5516-5531. [PMID: 36628288 PMCID: PMC9827090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 11/16/2022] [Indexed: 01/12/2023] Open
Abstract
Transforming Growth Factor beta (TGF-β) is a multifunctional cytokine that regulates cell proliferation, differentiation, and apoptosis. Dysregulation of the TGF-β signaling is one of the major mechanisms underlying tumor progression. We have previously reported that anaplastic lymphoma kinase (ALK) phosphorylates Smad4 at Tyr95, which compromises the DNA-binding ability of Smad4 and thus renders ALK-positive cancer cells resistant to TGF-β tumor-suppressive action. In this study, we demonstrated that tyrosine phosphatase PTPN2 positively regulated TGF-β signaling through dephosphorylating Smad4 at the Tyr95 site. Both in vitro and cell-based assays revealed that PTPN2 bound to and dephosphorylated Smad4, thereby preserving the DNA-binding ability of Smad4. Furthermore, overexpression of PTPN2 restored TGF-β transcriptional and growth inhibitory responses in ALK-positive cancer cells. Consistently, Spermidine, an activator of PTPN2, also promoted TGF-β-induced gene expression, apoptosis, and anti-proliferation effect. Taken together, we revealed that PTPN2 functioned as a tumor suppressor to antagonize the inhibitory effect of tyrosine phosphorylation of Smad4 and to ensure the proper TGF-β growth inhibitory signaling in cancer cells.
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Affiliation(s)
- Sujing Shi
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China,Center for Life Sciences, Shaoxing Institute, Zhejiang UniversityShaoxing 321000, Zhejiang, China,Cancer Center, Zhejiang UniversityHangzhou 310058, Zhejiang, China
| | - Dewei Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China,Center for Life Sciences, Shaoxing Institute, Zhejiang UniversityShaoxing 321000, Zhejiang, China,State Grid Zhejiang Electric Power Co., LtdHangzhou 310007, Zhejiang, China
| | - Shuchen Gu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China,Center for Life Sciences, Shaoxing Institute, Zhejiang UniversityShaoxing 321000, Zhejiang, China,Cancer Center, Zhejiang UniversityHangzhou 310058, Zhejiang, China
| | - Ningyi Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China,Center for Life Sciences, Shaoxing Institute, Zhejiang UniversityShaoxing 321000, Zhejiang, China,Westlake UniversityHangzhou 310024, Zhejiang, China
| | - Pinglong Xu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China,Center for Life Sciences, Shaoxing Institute, Zhejiang UniversityShaoxing 321000, Zhejiang, China,Cancer Center, Zhejiang UniversityHangzhou 310058, Zhejiang, China
| | - Jin Cao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China,Center for Life Sciences, Shaoxing Institute, Zhejiang UniversityShaoxing 321000, Zhejiang, China,Cancer Center, Zhejiang UniversityHangzhou 310058, Zhejiang, China
| | - Xin-Hua Feng
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang UniversityHangzhou 310058, Zhejiang, China,Center for Life Sciences, Shaoxing Institute, Zhejiang UniversityShaoxing 321000, Zhejiang, China,Cancer Center, Zhejiang UniversityHangzhou 310058, Zhejiang, China,The Second Affiliated Hospital, Zhejiang UniversityHangzhou 310009, Zhejiang, China
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15
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Song J, Lan J, Tang J, Luo N. PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review. Int J Mol Sci 2022; 23:ijms231710025. [PMID: 36077422 PMCID: PMC9456094 DOI: 10.3390/ijms231710025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/25/2022] [Accepted: 08/31/2022] [Indexed: 11/23/2022] Open
Abstract
PTPN2 (protein tyrosine phosphatase non-receptor 2), also called TCPTP (T cell protein tyrosine phosphatase), is a member of the PTP family signaling proteins. Phosphotyrosine-based signaling of this non-transmembrane protein is essential for regulating cell growth, development, differentiation, survival, and migration. In particular, PTPN2 received researchers’ attention when Manguso et al. identified PTPN2 as a cancer immunotherapy target using in vivo CRISPR library screening. In this review, we attempt to summarize the important functions of PTPN2 in terms of its structural and functional properties, inflammatory reactions, immunomodulatory properties, and tumor immunity. PTPN2 exerts synergistic anti-inflammatory effects in various inflammatory cells and regulates the developmental differentiation of immune cells. The diversity of PTPN2 effects in different types of tumors makes it a potential target for tumor immunotherapy.
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16
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Asare O, Ayala Y, Hafeez BB, Ramirez-Correa GA, Cho YY, Kim DJ. Ultraviolet Radiation Exposure and its Impacts on Cutaneous Phosphorylation Signaling in Carcinogenesis: Focusing on Protein Tyrosine Phosphatases †. Photochem Photobiol 2022; 99:344-355. [PMID: 36029171 DOI: 10.1111/php.13703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/23/2022] [Indexed: 01/14/2023]
Abstract
Sunlight exposure is a significant risk factor for UV-induced deteriorating transformations of epidermal homeostasis leading to skin carcinogenesis. The ability of UVB radiation to cause melanoma, as well as basal and squamous cell carcinomas, makes UVB the most harmful among the three known UV ranges. UVB-induced DNA mutations and dysregulation of signaling pathways contribute to skin cancer formation. Among various signaling pathways modulated by UVB, tyrosine phosphorylation signaling which is mediated by the action of protein tyrosine kinases (PTKs) on specific tyrosine residues is highly implicated in photocarcinogenesis. Following UVB irradiation, PTKs get activated and their downstream signaling pathways contribute to photocarcinogenesis by promoting the survival of damaged keratinocytes and increasing cell proliferation. While UVB activates oncogenic signaling pathways, it can also activate tumor suppressive signaling pathways as initial protective mechanisms to maintain epidermal homeostasis. Tyrosine dephosphorylation is one of the protective mechanisms and is mediated by the action of protein tyrosine phosphatases (PTPs). PTP can counteract UVB-mediated PTK activation and downregulate oncogenic signaling pathways. However, PTPs have not been studied extensively in photocarcinogenesis with previous studies regarding their inactivation induced by UVB. This current review will summarize the recent progress in the protective function of PTPs in epidermal photocarcinogenesis.
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Affiliation(s)
- Obed Asare
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX
| | - Yasmin Ayala
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX
| | - Bilal Bin Hafeez
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX.,South Texas Center for Excellence in Cancer Research, University of Texas Rio Grande Valley, Edinburg, TX
| | - Genaro A Ramirez-Correa
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX
| | - Yong-Yeon Cho
- College of Pharmacy, The Catholic University of Korea, Bucheon-si, Korea
| | - Dae Joon Kim
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX.,South Texas Center for Excellence in Cancer Research, University of Texas Rio Grande Valley, Edinburg, TX.,Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX
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17
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Tang X, Qi C, Zhou H, Liu Y. Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy. Front Oncol 2022; 12:972906. [PMID: 35957898 PMCID: PMC9360549 DOI: 10.3389/fonc.2022.972906] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/04/2022] [Indexed: 12/22/2022] Open
Abstract
Since tyrosine phosphorylation is reversible and dynamic in vivo, the phosphorylation state of proteins is controlled by the opposing roles of protein tyrosine kinases (PTKs) and protein tyrosine phosphatase (PTPs), both of which perform critical roles in signal transduction. Of these, intracellular non-receptor PTPs (PTPNs), which belong to the largest class I cysteine PTP family, are essential for the regulation of a variety of biological processes, including but not limited to hematopoiesis, inflammatory response, immune system, and glucose homeostasis. Additionally, a substantial amount of PTPNs have been identified to hold crucial roles in tumorigenesis, progression, metastasis, and drug resistance, and inhibitors of PTPNs have promising applications due to striking efficacy in antitumor therapy. Hence, the aim of this review is to summarize the role played by PTPNs, including PTPN1/PTP1B, PTPN2/TC-PTP, PTPN3/PTP-H1, PTPN4/PTPMEG, PTPN6/SHP-1, PTPN9/PTPMEG2, PTPN11/SHP-2, PTPN12/PTP-PEST, PTPN13/PTPL1, PTPN14/PEZ, PTPN18/PTP-HSCF, PTPN22/LYP, and PTPN23/HD-PTP, in human cancer and immunotherapy and to comprehensively describe the molecular pathways in which they are implicated. Given the specific roles of PTPNs, identifying potential regulators of PTPNs is significant for understanding the mechanisms of antitumor therapy. Consequently, this work also provides a review on the role of non-coding RNAs (ncRNAs) in regulating PTPNs in tumorigenesis and progression, which may help us to find effective therapeutic agents for tumor therapy.
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Affiliation(s)
- Xiaolong Tang
- Department of Clinical Laboratory Diagnostics, Binzhou Medical University, Binzhou, China
| | - Chumei Qi
- Department of Clinical Laboratory, Dazhou Women and Children’s Hospital, Dazhou, China
| | - Honghong Zhou
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- *Correspondence: Honghong Zhou, ; Yongshuo Liu,
| | - Yongshuo Liu
- Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
- *Correspondence: Honghong Zhou, ; Yongshuo Liu,
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18
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Goh PK, Wiede F, Zeissig MN, Britt KL, Liang S, Molloy T, Goode N, Xu R, Loi S, Muller M, Humbert PO, McLean C, Tiganis T. PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer. SCIENCE ADVANCES 2022; 8:eabk3338. [PMID: 35196085 PMCID: PMC8865802 DOI: 10.1126/sciadv.abk3338] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 12/24/2021] [Indexed: 05/22/2023]
Abstract
The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low PTPN2 associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1-dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC.
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Affiliation(s)
- Pei Kee Goh
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Florian Wiede
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Mara N. Zeissig
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Kara L. Britt
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Shuwei Liang
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Tim Molloy
- St. Vincent’s Centre for Applied Medical Research, Darlinghurst, New South Wales 2010, Australia
| | - Nathan Goode
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
| | - Rachel Xu
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Sherene Loi
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
| | - Mathias Muller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Patrick O. Humbert
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, Australia
- Research Centre for Molecular Cancer Prevention, La Trobe University, Melbourne, Victoria 3086, Australia
- Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia
- Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Catriona McLean
- Anatomical Pathology, Alfred Hospital, Prahran, Victoria 3004, Australia
| | - Tony Tiganis
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
- Corresponding author.
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19
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Karaca Atabay E, Mecca C, Wang Q, Ambrogio C, Mota I, Prokoph N, Mura G, Martinengo C, Patrucco E, Leonardi G, Hossa J, Pich A, Mologni L, Gambacorti-Passerini C, Brugières L, Geoerger B, Turner SD, Voena C, Cheong TC, Chiarle R. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma. Blood 2022; 139:717-731. [PMID: 34657149 PMCID: PMC8814675 DOI: 10.1182/blood.2020008136] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/28/2021] [Indexed: 02/05/2023] Open
Abstract
Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.
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Affiliation(s)
- Elif Karaca Atabay
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Carmen Mecca
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Qi Wang
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Chiara Ambrogio
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Ines Mota
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Nina Prokoph
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Giulia Mura
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Cinzia Martinengo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Enrico Patrucco
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Giulia Leonardi
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Jessica Hossa
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Achille Pich
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Luca Mologni
- Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | | | - Laurence Brugières
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Villejuif, France
| | - Birgit Geoerger
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Villejuif, France
- Department of Oncology for Children and Adolescents, Université Paris-Saclay, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8203, Villejuif, France; and
| | - Suzanne D Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
| | - Claudia Voena
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Taek-Chin Cheong
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Roberto Chiarle
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
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20
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Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment. Nutrients 2021; 14:nu14010079. [PMID: 35010954 PMCID: PMC8746460 DOI: 10.3390/nu14010079] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023] Open
Abstract
To date, the tumor microenvironment (TME) has gained considerable attention in various areas of cancer research due to its role in driving a loss of immune surveillance and enabling rapid advanced tumor development and progression. The TME plays an integral role in driving advanced aggressive breast cancers, including triple-negative breast cancer (TNBC), a pivotal mediator for tumor cells to communicate with the surrounding cells via lymphatic and circulatory systems. Furthermore, the TME plays a significant role in all steps and stages of carcinogenesis by promoting and stimulating uncontrolled cell proliferation and protecting tumor cells from the immune system. Various cellular components of the TME work together to drive cancer processes, some of which include tumor-associated adipocytes, fibroblasts, macrophages, and neutrophils which sustain perpetual amplification and release of pro-inflammatory molecules such as cytokines. Thymoquinone (TQ), a natural chemical component from black cumin seed, is widely used traditionally and now in clinical trials for the treatment/prevention of multiple types of cancer, showing a potential to mitigate components of TME at various stages by various pathways. In this review, we focus on the role of TME in TNBC cancer progression and the effect of TQ on the TME, emphasizing their anticipated role in the prevention and treatment of TNBC. It was concluded from this review that the multiple components of the TME serve as a critical part of TNBC tumor promotion and stimulation of uncontrolled cell proliferation. Meanwhile, TQ could be a crucial compound in the prevention and progression of TNBC therapy through the modulation of the TME.
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21
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Protein Tyrosine Phosphatases: Mechanisms in Cancer. Int J Mol Sci 2021; 22:ijms222312865. [PMID: 34884670 PMCID: PMC8657787 DOI: 10.3390/ijms222312865] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
Protein tyrosine kinases, especially receptor tyrosine kinases, have dominated the cancer therapeutics sphere as proteins that can be inhibited to selectively target cancer. However, protein tyrosine phosphatases (PTPs) are also an emerging target. Though historically known as negative regulators of the oncogenic tyrosine kinases, PTPs are now known to be both tumor-suppressive and oncogenic. This review will highlight key protein tyrosine phosphatases that have been thoroughly investigated in various cancers. Furthermore, the different mechanisms underlying pro-cancerous and anti-cancerous PTPs will also be explored.
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22
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La Marca JE, Willoughby LF, Allan K, Portela M, Goh PK, Tiganis T, Richardson HE. PTP61F Mediates Cell Competition and Mitigates Tumorigenesis. Int J Mol Sci 2021; 22:12732. [PMID: 34884538 PMCID: PMC8657627 DOI: 10.3390/ijms222312732] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/23/2021] [Accepted: 11/23/2021] [Indexed: 12/13/2022] Open
Abstract
Tissue homeostasis via the elimination of aberrant cells is fundamental for organism survival. Cell competition is a key homeostatic mechanism, contributing to the recognition and elimination of aberrant cells, preventing their malignant progression and the development of tumors. Here, using Drosophila as a model organism, we have defined a role for protein tyrosine phosphatase 61F (PTP61F) (orthologue of mammalian PTP1B and TCPTP) in the initiation and progression of epithelial cancers. We demonstrate that a Ptp61F null mutation confers cells with a competitive advantage relative to neighbouring wild-type cells, while elevating PTP61F levels has the opposite effect. Furthermore, we show that knockdown of Ptp61F affects the survival of clones with impaired cell polarity, and that this occurs through regulation of the JAK-STAT signalling pathway. Importantly, PTP61F plays a robust non-cell-autonomous role in influencing the elimination of adjacent polarity-impaired mutant cells. Moreover, in a neoplastic RAS-driven polarity-impaired tumor model, we show that PTP61F levels determine the aggressiveness of tumors, with Ptp61F knockdown or overexpression, respectively, increasing or reducing tumor size. These effects correlate with the regulation of the RAS-MAPK and JAK-STAT signalling by PTP61F. Thus, PTP61F acts as a tumor suppressor that can function in an autonomous and non-cell-autonomous manner to ensure cellular fitness and attenuate tumorigenesis.
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Affiliation(s)
- John E. La Marca
- Cell Polarity, Cell Signaling & Cancer Laboratory, Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (J.E.L.M.); (K.A.); (M.P.)
| | - Lee F. Willoughby
- Cell Cycle & Development Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia;
| | - Kirsten Allan
- Cell Polarity, Cell Signaling & Cancer Laboratory, Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (J.E.L.M.); (K.A.); (M.P.)
| | - Marta Portela
- Cell Polarity, Cell Signaling & Cancer Laboratory, Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (J.E.L.M.); (K.A.); (M.P.)
| | - Pei Kee Goh
- Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (P.K.G.); (T.T.)
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
| | - Tony Tiganis
- Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (P.K.G.); (T.T.)
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
| | - Helena E. Richardson
- Cell Polarity, Cell Signaling & Cancer Laboratory, Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; (J.E.L.M.); (K.A.); (M.P.)
- Cell Cycle & Development Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia;
- Peter MacCallum Department of Oncology, Department of Anatomy & Neuroscience, Department of Biochemistry, University of Melbourne, Melbourne, VIC 3010, Australia
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23
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Nifuroxazide Mitigates Angiogenesis in Ehlrich's Solid Carcinoma: Molecular Docking, Bioinformatic and Experimental Studies on Inhibition of Il-6/Jak2/Stat3 Signaling. Molecules 2021; 26:molecules26226858. [PMID: 34833950 PMCID: PMC8621155 DOI: 10.3390/molecules26226858] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/12/2022] Open
Abstract
Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich’s mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich’s solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-β, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.
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24
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Sabaawy HE, Ryan BM, Khiabanian H, Pine SR. JAK/STAT of all trades: Linking inflammation with cancer development, tumor progression, and therapy resistance. Carcinogenesis 2021; 42:1411-1419. [PMID: 34415330 DOI: 10.1093/carcin/bgab075] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 08/04/2021] [Accepted: 08/18/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is at the forefront of carcinogenesis, tumor progression, and resistance to therapy. The JAK/STAT signaling axis is a central pathway that mediates the cellular response to inflammation and contributes to carcinogenesis. The JAK/STAT pathway coordinates intercellular communication between tumor cells and their immune microenvironment, and JAK/STAT activation leads to the expression of a variety of proteins involved in cell proliferation, cell survival, stemness, self-renewal, evasion of immunosurveillance mechanisms, and overall tumor progression. Activation of JAK/STAT signaling also mediates resistance to radiation therapy or cytotoxic agents, and modulates tumor cell responses to molecularly targeted and immune modulating drugs. Despite extensive research focused on understanding its signaling mechanisms and downstream phenotypic and functional consequences in hematological disorders, the importance of JAK/STAT signaling in solid tumor initiation and progression has been underappreciated. We highlight the role of chronic inflammation in cancer, the epidemiological evidence for contribution of JAK/STAT to carcinogenesis, the current cancer prevention measures involving JAK/STAT inhibition, and the impact of JAK/STAT signaling activity on cancer development, progression, and treatment resistance. We also discuss recent therapeutic advances in targeting key factors within the JAK/STAT pathway with single agents, and the use of these agents in combination with other targeted therapies and immune checkpoint inhibitors.
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Affiliation(s)
- Hatem E Sabaawy
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States.,Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States.,Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
| | - Bríd M Ryan
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
| | - Hossein Khiabanian
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States.,Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
| | - Sharon R Pine
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States.,Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States.,Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
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25
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Wang YN, Liu S, Jia T, Feng Y, Xu X, Zhang D. T Cell Protein Tyrosine Phosphatase in Glucose Metabolism. Front Cell Dev Biol 2021; 9:682947. [PMID: 34268308 PMCID: PMC8276021 DOI: 10.3389/fcell.2021.682947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/09/2021] [Indexed: 11/17/2022] Open
Abstract
T cell protein tyrosine phosphatase (TCPTP), a vital regulator in glucose metabolism, inflammatory responses, and tumor processes, is increasingly considered a promising target for disease treatments and illness control. This review discusses the structure, substrates and main biological functions of TCPTP, as well as its regulatory effect in glucose metabolism, as an attempt to be referenced for formulating treatment strategies of metabolic disorders. Given the complicated regulation functions in different tissues and organs of TCPTP, the development of drugs inhibiting TCPTP with a higher specificity and a better biocompatibility is recognized as a promising therapeutic strategy for diabetes or obesity. Besides, treatments targeting TCPTP in a specific tissue or organ are suggested to be considerably promising.
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Affiliation(s)
- Ya-Nan Wang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Shiyue Liu
- Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.,Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingting Jia
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Yao Feng
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Xin Xu
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dongjiao Zhang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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26
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Zhao W, Hao L, Jia L, Wang J, Wang B, Huang Y, Zhao Y. TAFs contributes the function of PTPN2 in colorectal carcinogenesis through activating JAK/STAT signaling pathway. Am J Cancer Res 2021; 11:3085-3097. [PMID: 34249446 PMCID: PMC8263690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/01/2021] [Indexed: 06/13/2023] Open
Abstract
The morbidity and mortality of colorectal cancer (CRC) ranks fourth worldwide, moreover, the tumor microenvironment (TME) of CRC is quite complex, and is one of the necessary factors affecting promotion of tumor metastasis. PTPN2 is a tumor suppressor which plays an important role in cancer-related downstream molecular pathway. FSP-1 is highly-expressed in multiple types of tumor tissues and is a biomarker of stromal fibroblasts. To examine the function of PTPN2 in the metastasis of CRC, the study evaluated the co-expression level of PTPN2 and FSP-1 in CRC tissues by double staining, and demonstrated the relationship with clinical information about each patient. The roles of PTPN2 and FSP-1 were detected in vitro by proliferation and transwell assay through knockdown of expression level of PTPN2. Lower PTPN2 with higher FSP-1 expression was correlated with poor survival outcomes in CRC. TAFs contribute to the migration function of PTPN2 in CRC in vitro through inducing changes in the level of TGF-β1. Western blot and qRT-PCR assays were used to detect the mechanism of PTPN2 regulation of migration with TAFs in the JAK/STAT signaling pathway, moreover, TAFs contributed the function of PTPN2 in colorectal carcinogenesis in vivo. In summary, the study shed light on the effect of TAFs contributes the function of PTPN2 in colorectal carcinogenesis through activating JAK/STAT signaling pathway. In addition, double-staining assay could give us a unique perspective from which to study TME in CRC.
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Affiliation(s)
- Wei Zhao
- Research Center for The Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for NationalitiesBaise 533000, China
- Department of Pathology, Nanjing First Hospital, Nanjing Medical UniversityNanjing 210006, China
| | - Lei Hao
- Department of Pathophysiology, Inner Mongolia Medical UniversityInner Mongolia 010059, China
| | - Lizhou Jia
- Research Center for The Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for NationalitiesBaise 533000, China
- Central Laboratory, Bayannur HospitalInner Mongolia 015000, China
| | - Jinsong Wang
- Department of Pathology, Nanjing First Hospital, Nanjing Medical UniversityNanjing 210006, China
| | - Bin Wang
- Department of Pathology, Nanjing First Hospital, Nanjing Medical UniversityNanjing 210006, China
| | - Yanqiang Huang
- Research Center for The Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for NationalitiesBaise 533000, China
| | - Youcai Zhao
- Department of Pathology, Nanjing First Hospital, Nanjing Medical UniversityNanjing 210006, China
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27
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Flosbach M, Oberle SG, Scherer S, Zecha J, von Hoesslin M, Wiede F, Chennupati V, Cullen JG, List M, Pauling JK, Baumbach J, Kuster B, Tiganis T, Zehn D. PTPN2 Deficiency Enhances Programmed T Cell Expansion and Survival Capacity of Activated T Cells. Cell Rep 2020; 32:107957. [PMID: 32726622 PMCID: PMC7408006 DOI: 10.1016/j.celrep.2020.107957] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/20/2020] [Accepted: 07/02/2020] [Indexed: 01/18/2023] Open
Abstract
Manipulating molecules that impact T cell receptor (TCR) or cytokine signaling, such as the protein tyrosine phosphatase non-receptor type 2 (PTPN2), has significant potential for advancing T cell-based immunotherapies. Nonetheless, it remains unclear how PTPN2 impacts the activation, survival, and memory formation of T cells. We find that PTPN2 deficiency renders cells in vivo and in vitro less dependent on survival-promoting cytokines, such as interleukin (IL)-2 and IL-15. Remarkably, briefly ex vivo-activated PTPN2-deficient T cells accumulate in 3- to 11-fold higher numbers following transfer into unmanipulated, antigen-free mice. Moreover, the absence of PTPN2 augments the survival of short-lived effector T cells and allows them to robustly re-expand upon secondary challenge. Importantly, we find no evidence for impaired effector function or memory formation. Mechanistically, PTPN2 deficiency causes broad changes in the expression and phosphorylation of T cell expansion and survival-associated proteins. Altogether, our data underline the therapeutic potential of targeting PTPN2 in T cell-based therapies to augment the number and survival capacity of antigen-specific T cells.
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Affiliation(s)
- Markus Flosbach
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Susanne G Oberle
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Stefanie Scherer
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany; Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Jana Zecha
- Chair of Proteomics and Bioanalytics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Madlaina von Hoesslin
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Florian Wiede
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
| | - Vijaykumar Chennupati
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Jolie G Cullen
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Markus List
- Big Data in BioMedicine Group, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Josch K Pauling
- ZD.B Junior Research Group LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Jan Baumbach
- Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Bernhard Kuster
- Chair of Proteomics and Bioanalytics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Tony Tiganis
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
| | - Dietmar Zehn
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany; Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
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28
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Kim M, Morales LD, Lee CJ, Olivarez SA, Kim WJ, Hernandez J, Mummidi S, Jenkinson C, Tsin AT, Jang IS, Slaga TJ, Kim DJ. Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation. Oncogene 2020; 39:4241-4256. [PMID: 32286519 PMCID: PMC7244373 DOI: 10.1038/s41388-020-1282-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 03/18/2020] [Accepted: 03/23/2020] [Indexed: 02/07/2023]
Abstract
T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, has been shown to function as a tumor suppressor during skin carcinogenesis. In the current study, we generated a novel epidermal-specific TC-PTP-overexpressing (K5HA.Ptpn2) mouse model to show that TC-PTP contributes to the attenuation of chemically induced skin carcinogenesis through the synergistic regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling. We found overexpression of TC-PTP increased epidermal sensitivity to DMBA-induced apoptosis and it decreased TPA-mediated hyperproliferation, coinciding with reduced epidermal thickness. Inhibition of STAT1, STAT3, STAT5, or AKT reversed the effects of TC-PTP overexpression on epidermal survival and proliferation. Mice overexpressing TC-PTP in the epidermis developed significantly reduced numbers of tumors during skin carcinogenesis and presented a prolonged latency of tumor initiation. Examination of human papillomas and squamous cell carcinomas (SCCs) revealed that TC-PTP expression was significantly reduced and TC-PTP expression was inversely correlated with the increased grade of SCCs. Our findings demonstrate that TC-PTP is a potential therapeutic target for the prevention of human skin cancer given that it is a major negative regulator of oncogenic signaling.
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Affiliation(s)
- Mihwa Kim
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Liza D Morales
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Cheol Jung Lee
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Serena A Olivarez
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Woo Jin Kim
- School of Mathematical and Statistical Sciences, College of Sciences, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Joselin Hernandez
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Srinivas Mummidi
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Christopher Jenkinson
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Andrew T Tsin
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Ik-Soon Jang
- Division of Bioconvergence Analysis, Korea Basic Science Institute, Daejeon, 305-333, Republic of Korea
| | - Thomas J Slaga
- Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Dae Joon Kim
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA.
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA.
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29
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Wiede F, Lu K, Du X, Liang S, Hochheiser K, Dodd GT, Goh PK, Kearney C, Meyran D, Beavis PA, Henderson MA, Park SL, Waithman J, Zhang S, Zhang Z, Oliaro J, Gebhardt T, Darcy PK, Tiganis T. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J 2020; 39:e103637. [PMID: 31803974 PMCID: PMC6960448 DOI: 10.15252/embj.2019103637] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/04/2019] [Accepted: 11/08/2019] [Indexed: 12/18/2022] Open
Abstract
Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR T-cell activation and homing to CXCL9/10-expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell-mediated anti-tumour immunity and CAR T-cell therapy against solid tumours.
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Affiliation(s)
- Florian Wiede
- Monash Biomedicine Discovery InstituteMonash UniversityClaytonVic.Australia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVic.Australia
- Peter MacCallum Cancer CentreMelbourneVic.Australia
| | - Kun‐Hui Lu
- Peter MacCallum Cancer CentreMelbourneVic.Australia
| | - Xin Du
- Peter MacCallum Cancer CentreMelbourneVic.Australia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVic.Australia
| | - Shuwei Liang
- Monash Biomedicine Discovery InstituteMonash UniversityClaytonVic.Australia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVic.Australia
- Peter MacCallum Cancer CentreMelbourneVic.Australia
| | - Katharina Hochheiser
- Peter MacCallum Cancer CentreMelbourneVic.Australia
- Department of Microbiology and ImmunologyThe University of MelbourneMelbourneVic.Australia
- Peter Doherty Institute for Infection and ImmunityMelbourneVic.Australia
| | - Garron T Dodd
- Monash Biomedicine Discovery InstituteMonash UniversityClaytonVic.Australia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVic.Australia
| | - Pei K Goh
- Monash Biomedicine Discovery InstituteMonash UniversityClaytonVic.Australia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVic.Australia
- Peter MacCallum Cancer CentreMelbourneVic.Australia
| | | | | | - Paul A Beavis
- Peter MacCallum Cancer CentreMelbourneVic.Australia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVic.Australia
| | | | - Simone L Park
- Department of Microbiology and ImmunologyThe University of MelbourneMelbourneVic.Australia
- Peter Doherty Institute for Infection and ImmunityMelbourneVic.Australia
| | - Jason Waithman
- Telethon Kids InstituteUniversity of Western AustraliaPerthWAAustralia
| | - Sheng Zhang
- Department of Medicinal Chemistry and Molecular PharmacologyInstitute for Drug DiscoveryPurdue UniversityWest LafayetteINUSA
| | - Zhong‐Yin Zhang
- Department of Medicinal Chemistry and Molecular PharmacologyInstitute for Drug DiscoveryPurdue UniversityWest LafayetteINUSA
| | - Jane Oliaro
- Peter MacCallum Cancer CentreMelbourneVic.Australia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVic.Australia
| | - Thomas Gebhardt
- Department of Microbiology and ImmunologyThe University of MelbourneMelbourneVic.Australia
- Peter Doherty Institute for Infection and ImmunityMelbourneVic.Australia
| | - Phillip K Darcy
- Peter MacCallum Cancer CentreMelbourneVic.Australia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVic.Australia
| | - Tony Tiganis
- Monash Biomedicine Discovery InstituteMonash UniversityClaytonVic.Australia
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVic.Australia
- Peter MacCallum Cancer CentreMelbourneVic.Australia
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Zhu X, Zhang Y, Bai Y, Gu X, Chen G, Sun L, Wang Y, Qiao X, Ma Q, Zhu T, Bu J, Xue J, Liu C. HCK can serve as novel prognostic biomarker and therapeutic target for Breast Cancer patients. Int J Med Sci 2020; 17:2773-2789. [PMID: 33162805 PMCID: PMC7645343 DOI: 10.7150/ijms.43161] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 09/16/2020] [Indexed: 01/10/2023] Open
Abstract
The role of HCK expression in the prognosis of breast cancer patients is unclear. Thus, this study aimed to explore the clinical implications of HCK expression in breast cancer. We assessed HCK expression and genetic variations in breast cancer using Oncomine, GEPIA, UALCAN, and cBioPortal databases. Then, immunochemistry was used to analyze HCK expression in breast cancer specimens, non-cancer tissues and metastatic cancer tissues. Consequently, we evaluated the effect of HCK expression on survival outcomes set as disease-free survival (DFS) and overall survival (OS). Finally, STRING, Coexpedia, and TISIDB database were explored to identify the molecular functions and regulation pathways of HCK. We found that breast cancer tissues have more HCK mRNA transcripts than non-cancer tissues. Patients with HCK expression had significantly shorter DFS and OS. The ratio of HCK expression was higher in cancer tissues than in non-cancer tissues. These results from STRING database, FunRich software, and TISIDB database showed that HCK was involved in mediating multiple biological processes including immune response-regulating signaling pathway, cell growth and maintenance through multiple signaling pathways including epithelial to mesenchymal transition, PI3K/AKT signaling pathway, and focal adhesion. Overall, HCK may be an oncogene in the development of breast cancer and thus may as a novel biomarker and therapeutic target for breast cancer.
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Affiliation(s)
- Xudong Zhu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Yixiao Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Yang Bai
- Department of Operating Room, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Xi Gu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Guanglei Chen
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Lisha Sun
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Yulun Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Xinbo Qiao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Qingtian Ma
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Tong Zhu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Jiawen Bu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Jinqi Xue
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Caigang Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
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Chang-Qing Y, Jie L, Shi-Qi Z, Kun Z, Zi-Qian G, Ran X, Hui-Meng L, Ren-Bin Z, Gang Z, Da-Chuan Y, Chen-Yan Z. Recent treatment progress of triple negative breast cancer. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2019; 151:40-53. [PMID: 31761352 DOI: 10.1016/j.pbiomolbio.2019.11.007] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 09/24/2019] [Accepted: 11/13/2019] [Indexed: 12/24/2022]
Abstract
Breast cancer (BC) is a serious worldwide disease that threatens women's health. Particularly, the morbidity of triple-negative breast cancer (TNBC) is higher than that of other BC types due to its high molecular heterogeneity, metastatic potential and poor prognosis. TNBC lacks of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), so there are still no effective treatment methods for TNBC. Here, we reviewed the classification of TNBC, its molecular mechanisms of pathogenesis, treatment methods and prognosis. Finding effective targets is critical for the treatment of TNBC. Also, refining the classification of TNBC is benefited to choose the treatment of TNBC, because the sensitivity of chemotherapy is different in different TNBC. Some new treatment methods have been proposed in recent years, such as nutritional therapy and noncoding RNA treatment methods. There are some disadvantages, such as the side effect on normal cells after nutrient deprivation, low specificity and instability of noncoding RNA. More studies are necessary to improve the treatment of TNBC.
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Affiliation(s)
- Yang Chang-Qing
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Liu Jie
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Zhao Shi-Qi
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Zhu Kun
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Gong Zi-Qian
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Xu Ran
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Lu Hui-Meng
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Zhou Ren-Bin
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China
| | - Zhao Gang
- The First Hospital of Jilin University, Changchun, Jilin Province, 130021, PR China.
| | - Yin Da-Chuan
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China.
| | - Zhang Chen-Yan
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, PR China.
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Morales LD, Archbold AK, Olivarez S, Slaga TJ, DiGiovanni J, Kim DJ. The role of T-cell protein tyrosine phosphatase in epithelial carcinogenesis. Mol Carcinog 2019; 58:1640-1647. [PMID: 31264291 PMCID: PMC6692238 DOI: 10.1002/mc.23078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 02/06/2023]
Abstract
T-cell protein tyrosine phosphatase (TC-PTP, encoded by PTPN2) is a nonreceptor PTP that is most highly expressed in hematopoietic tissues. TC-PTP modulates a variety of physiological functions including cell cycle progression, cell survival and proliferation, and hematopoiesis through tyrosine dephosphorylation of its target substrates, such as EGFR, JAK1, JAK3, STAT1, and STAT3. Studies with whole or tissue-specific loss of TC-PTP function transgenic mice have shown that TC-PTP has crucial roles in the regulation of the immune response, insulin signaling, and oncogenic signaling. More recently, the generation of epidermal-specific TC-PTP-deficient mice for use in multistage skin carcinogenesis bioassays demonstrated that TC-PTP suppresses skin tumor formation by negatively regulating STAT3 and AKT signaling. Further investigation showed that TC-PTP also minimizes UVB-induced epidermal cell damage by promoting apoptosis through the negative regulation of Flk-1/JNK signaling. These findings provide major evidence for a tumor suppressive function for TC-PTP against environment-induced skin cancer. Here, we will discuss TC-PTP, its substrates, and its functions with an emphasis on its role in skin carcinogenesis.
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Affiliation(s)
- Liza D. Morales
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA
- South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA
| | - Anna K. Archbold
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA
| | - Serena Olivarez
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA
| | - Thomas J. Slaga
- Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - John DiGiovanni
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78723, USA
| | - Dae Joon Kim
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA
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Zhang D, Jiang Y, Song D, Zhu Z, Zhou C, Dai L, Xu X. Tyrosine-protein phosphatase non-receptor type 2 inhibits alveolar bone resorption in diabetic periodontitis via dephosphorylating CSF1 receptor. J Cell Mol Med 2019; 23:6690-6699. [PMID: 31373168 PMCID: PMC6787442 DOI: 10.1111/jcmm.14545] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 06/12/2019] [Accepted: 06/28/2019] [Indexed: 01/07/2023] Open
Abstract
Tyrosine-protein phosphatase non-receptor type 2 (PTPN2) is an important protection factor for diabetes and periodontitis, but the underlying mechanism remains elusive. This study aimed to identify the substrate of PTPN2 in mediating beneficial effects of 25-Hydroxyvitamin D3 (25(OH)2D3 ) on diabetic periodontitis. 25(OH)2D3 photo-affinity probe was synthesized with the minimalist linker and its efficacy to inhibit alveolar bone loss, and inflammation was evaluated in diabetic periodontitis mice. The probe was used to pull down the lysates of primary gingival fibroblasts. We identified PTPN2 as a direct target of 25(OH)2D3 , which effectively inhibited inflammation and bone resorption in diabetic periodontitis mice. In addition, we found that colony-stimulating factor 1 receptor (CSF1R) rather than JAK/STAT was the substrate of PTPN2 to regulate bone resorption. PTPN2 direct interacted with CSF1R and dephosphorylated Tyr807 residue. In conclusion, PTPN2 dephosphorylates CSF1R at Y807 site and inhibits alveolar bone resorption in diabetic periodontitis mice. PTPN2 and CSF1R are potential targets for the therapy of diabetic periodontitis or other bone loss-related diseases.
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Affiliation(s)
- Dongjiao Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China.,Department of Implantology, School of Stomatology, Shandong University, Jinan, China
| | - Yanfei Jiang
- Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Dawei Song
- The Seventh People's Hospital of Shenzhen, Shenzhen, China
| | - Zhenkun Zhu
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China.,Department of Implantology, School of Stomatology, Shandong University, Jinan, China
| | - Cong Zhou
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China.,Department of Implantology, School of Stomatology, Shandong University, Jinan, China
| | - Li Dai
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China.,Department of Implantology, School of Stomatology, Shandong University, Jinan, China
| | - Xin Xu
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China.,Department of Implantology, School of Stomatology, Shandong University, Jinan, China
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34
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3D-QSAR, molecular docking, and new compound design of pyrimidine derivatives as Src small molecule inhibitors. Med Chem Res 2019. [DOI: 10.1007/s00044-019-02370-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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35
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Hamel-Côté G, Lapointe F, Véronneau S, Mayhue M, Rola-Pleszczynski M, Stankova J. Regulation of platelet-activating factor-mediated interleukin-6 promoter activation by the 48 kDa but not the 45 kDa isoform of protein tyrosine phosphatase non-receptor type 2. Cell Biosci 2019; 9:51. [PMID: 31289638 PMCID: PMC6593612 DOI: 10.1186/s13578-019-0316-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/20/2019] [Indexed: 12/20/2022] Open
Abstract
Background An underlying state of inflammation is thought to be an important cause of cardiovascular disease. Among cells involved in the early steps of atherosclerosis, monocyte-derived dendritic cells (Mo-DCs) respond to inflammatory stimuli, including platelet-activating factor (PAF), by the induction of various cytokines, such as interleukin 6 (IL-6). PAF is a potent phospholipid mediator involved in both the onset and progression of atherosclerosis. It mediates its effects by binding to its cognate G-protein coupled receptor, PAFR. Activation of PAFR-induced signaling pathways is tightly coordinated to ensure specific cell responses. Results Here, we report that PAF stimulated the phosphatase activity of both the 45 and 48 kDa isoforms of the protein tyrosine phosphatase non-receptor type 2 (PTPN2). However, we found that only the 48 kDa PTPN2 isoform has a role in PAFR-induced signal transduction, leading to activation of the IL-6 promoter. In luciferase reporter assays, expression of the 48 kDa, but not the 45 kDa, PTPN2 isoform increased human IL-6 (hIL-6) promoter activity by 40% after PAF stimulation of HEK-293 cells, stably transfected with PAFR (HEK-PAFR). Our results suggest that the differential localization of the PTPN2 isoforms and the differences in PAF-induced phosphatase activation may contribute to the divergent modulation of PAF-induced IL-6 promoter activation. The involvement of PTPN2 in PAF-induced IL-6 expression was confirmed in immature Mo-DCs (iMo-DCs), using siRNAs targeting the two isoforms of PTPN2, where siRNAs against the 48 kDa PTPN2 significantly inhibited PAF-stimulated IL-6 mRNA expression. Pharmacological inhibition of several signaling pathways suggested a role for PTPN2 in early signaling events. Results obtained by Western blot confirmed that PTPN2 increased the activation of the PI3K/Akt pathway via the modulation of protein kinase D (PKD) activity. WT PKD expression counteracted the effect of PTPN2 on PAF-induced IL-6 promoter transactivation and phosphorylation of Akt. Using siRNAs targeting the individual isoforms of PTPN2, we confirmed that these pathways were also active in iMo-DCs. Conclusion Taken together, our data suggest that PTPN2, in an isoform-specific manner, could be involved in the positive regulation of PI3K/Akt activation, via the modulation of PKD activity, allowing for the maximal induction of PAF-stimulated IL-6 mRNA expression.
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Affiliation(s)
- Geneviève Hamel-Côté
- Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC Canada
| | - Fanny Lapointe
- Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC Canada
| | - Steeve Véronneau
- Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC Canada
| | - Marian Mayhue
- Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC Canada
| | - Marek Rola-Pleszczynski
- Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC Canada
| | - Jana Stankova
- Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC Canada
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Wu M, Song D, Li H, Yang Y, Ma X, Deng S, Ren C, Shu X. Negative regulators of STAT3 signaling pathway in cancers. Cancer Manag Res 2019; 11:4957-4969. [PMID: 31213912 PMCID: PMC6549392 DOI: 10.2147/cmar.s206175] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 04/17/2019] [Indexed: 12/19/2022] Open
Abstract
STAT3 is the most ubiquitous member of the STAT family and involved in many biological processes, such as cell proliferation, differentiation, and apoptosis. Mounting evidence has revealed that STAT3 is aberrantly activated in many malignant tumors and plays a critical role in cancer progression. STAT3 is usually regarded as an effective molecular target for cancer treatment, and abolishing the STAT3 activity may diminish tumor growth and metastasis. Recent studies have shown that negative regulators of STAT3 signaling such as PIAS, SOCS, and PTP, can effectively retard tumor progression. However, PIAS, SOCS, and PTP have also been reported to correlate with tumor malignancy, and their biological function in tumorigenesis and antitumor therapy are somewhat controversial. In this review, we summarize actual knowledge on the negative regulators of STAT3 in tumors, and focus on the potential role of PIAS, SOCS, and PTP in cancer treatment. Furthermore, we also outline the STAT3 inhibitors that have entered clinical trials. Targeting STAT3 seems to be a promising strategy in cancer therapy.
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Affiliation(s)
- Moli Wu
- College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China.,College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Danyang Song
- College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Hui Li
- College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Yang Yang
- College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Xiaodong Ma
- College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Sa Deng
- College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Changle Ren
- Surgery Department of Dalian Municipal Central Hospital, Dalian Medical University, Dalian 116033, People's Republic of China
| | - Xiaohong Shu
- College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China
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Qin JJ, Yan L, Zhang J, Zhang WD. STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:195. [PMID: 31088482 PMCID: PMC6518732 DOI: 10.1186/s13046-019-1206-z] [Citation(s) in RCA: 256] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 05/02/2019] [Indexed: 12/24/2022]
Abstract
Triple negative breast cancer (TNBC), which is typically lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), represents the most aggressive and mortal subtype of breast cancer. Currently, only a few treatment options are available for TNBC due to the absence of molecular targets, which underscores the need for developing novel therapeutic and preventive approaches for this disease. Recent evidence from clinical trials and preclinical studies has demonstrated a pivotal role of signal transducer and activator of transcription 3 (STAT3) in the initiation, progression, metastasis, and immune evasion of TNBC. STAT3 is overexpressed and constitutively activated in TNBC cells and contributes to cell survival, proliferation, cell cycle progression, anti-apoptosis, migration, invasion, angiogenesis, chemoresistance, immunosuppression, and stem cells self-renewal and differentiation by regulating the expression of its downstream target genes. STAT3 small molecule inhibitors have been developed and shown excellent anticancer activities in in vitro and in vivo models of TNBC. This review discusses the recent advances in the understanding of STAT3, with a focus on STAT3’s oncogenic role in TNBC. The current targeting strategies and representative small molecule inhibitors of STAT3 are highlighted. We also propose potential strategies that can be further examined for developing more specific and effective inhibitors for TNBC prevention and therapy.
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Affiliation(s)
- Jiang-Jiang Qin
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, China.
| | - Li Yan
- School of Pharmacy, Naval Medical University, 325 Guohe Road, Yangpu District, Shanghai, 200433, China
| | - Jia Zhang
- Shanxi Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Wei-Dong Zhang
- School of Pharmacy, Naval Medical University, 325 Guohe Road, Yangpu District, Shanghai, 200433, China. .,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Veenstra C, Karlsson E, Mirwani SM, Nordenskjöld B, Fornander T, Pérez-Tenorio G, Stål O. The effects of PTPN2 loss on cell signalling and clinical outcome in relation to breast cancer subtype. J Cancer Res Clin Oncol 2019; 145:1845-1856. [PMID: 31025094 PMCID: PMC6571101 DOI: 10.1007/s00432-019-02918-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 04/15/2019] [Indexed: 11/28/2022]
Abstract
Purpose The protein tyrosine phosphatase PTPN2 dephosphorylates several tyrosine kinases in cancer-related signalling pathways and is thought to be a tumour suppressor. As PTPN2 is not frequently studied in breast cancer, we aimed to explore the role of PTPN2 and the effects of its loss in breast cancer. Methods Protein expression and gene copy number of PTPN2 were analysed in a cohort of pre-menopausal breast cancer patients with immunohistochemistry and droplet digital PCR, respectively. PTPN2 was knocked down in three cell lines, representing different breast cancer subtypes, with siRNA transfection. Several proteins related to PTPN2 were analysed with Western blot. Results Low PTPN2 protein expression was found in 50.2% of the tumours (110/219), gene copy loss in 15.4% (33/214). Low protein expression was associated with a higher relapse rate in patients with Luminal A and HER2-positive tumours, but not triple-negative tumours. In vitro studies further suggested a subtype-specific role of PTPN2. Knockdown of PTPN2 had no effect on the triple-negative cell line, whilst knockdown in MCF7 inhibited phosphorylation of Met and promoted that of Akt. Knockdown in SKBR3 led to increased Met phosphorylation and decreased Erk phosphorylation as well as EGF-mediated STAT3 activation. Conclusion We confirm previous studies showing that the PTPN2 protein is lost in half of the breast cancer cases and gene deletion occurs in 15–18% of the cases. Furthermore, the results suggest that the role of PTPN2 is subtype-related and should be further investigated to assess how this could affect breast cancer prognosis and treatment response.
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Affiliation(s)
- Cynthia Veenstra
- Division of Clinical Sciences, Department of Clinical and Experimental Medicine and Department of Oncology, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden.
| | - Elin Karlsson
- Division of Clinical Sciences, Department of Clinical and Experimental Medicine and Department of Oncology, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden
| | - Sanam Mirwani Mirwani
- Division of Clinical Sciences, Department of Clinical and Experimental Medicine and Department of Oncology, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden
| | - Bo Nordenskjöld
- Division of Clinical Sciences, Department of Clinical and Experimental Medicine and Department of Oncology, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden
| | - Tommy Fornander
- Department of Oncology-Pathology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden
| | - Gizeh Pérez-Tenorio
- Division of Clinical Sciences, Department of Clinical and Experimental Medicine and Department of Oncology, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden
| | - Olle Stål
- Division of Clinical Sciences, Department of Clinical and Experimental Medicine and Department of Oncology, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden
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Wu D, Lv D, Zhang T, Guo L, Ma F, Zhang C, Lv G, Huang L. Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor. Endocr Relat Cancer 2019; 26:187-199. [PMID: 30422809 PMCID: PMC6347285 DOI: 10.1530/erc-18-0370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 11/12/2018] [Indexed: 12/20/2022]
Abstract
Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein β-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. β-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of β-elemene on IR signaling pathway. β-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by β-elemene specifically in tumor cells other than normal hepatocytes. In addition, β-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the β-elemene-treated xenografts. These data suggest that β-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by β-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors.
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Affiliation(s)
- Dawei Wu
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Dongwei Lv
- Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Ting Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Lianying Guo
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Fangli Ma
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Caihua Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Guofeng Lv
- Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
- Correspondence should be addressed to L Huang or G Lv: or
| | - Lin Huang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
- Correspondence should be addressed to L Huang or G Lv: or
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Ellegård S, Veenstra C, Pérez-Tenorio G, Fagerström V, Gårsjö J, Gert K, Sundquist M, Malmström A, Wingren S, Elander NO, Hallbeck AL, Stål O. ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab. Oncol Lett 2019; 17:3371-3381. [PMID: 30867772 PMCID: PMC6396168 DOI: 10.3892/ol.2019.9998] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 12/20/2018] [Indexed: 12/25/2022] Open
Abstract
Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linköping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of ≥6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2–0.9] and progression-free survival (HR=0.3; 95% CI: 0.1–0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (≥3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0–4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0–4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.
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Affiliation(s)
- Sander Ellegård
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Cynthia Veenstra
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Gizeh Pérez-Tenorio
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Victor Fagerström
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden.,Department of Surgery, Kalmar Hospital, SE-392 44 Kalmar, Sweden
| | - Jon Gårsjö
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Krista Gert
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Marie Sundquist
- Department of Surgery, Kalmar Hospital, SE-392 44 Kalmar, Sweden
| | - Annika Malmström
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Sten Wingren
- Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, SE-701 82 Örebro, Sweden
| | - Nils O Elander
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Anna-Lotta Hallbeck
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
| | - Olle Stål
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, SE-581 85 Linköping, Sweden
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Karlsson E, Veenstra C, Gårsjö J, Nordenskjöld B, Fornander T, Stål O. PTPN2 deficiency along with activation of nuclear Akt predict endocrine resistance in breast cancer. J Cancer Res Clin Oncol 2018; 145:599-607. [PMID: 30515568 PMCID: PMC6394658 DOI: 10.1007/s00432-018-2810-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 11/30/2018] [Indexed: 01/18/2023]
Abstract
Purpose The protein tyrosine phosphatase, non-receptor type 2 (PTNP2) regulates receptor tyrosine kinase signalling, preventing downstream activation of intracellular pathways like the PI3K/Akt pathway. The gene encoding the protein is located on chromosome 18p11; the 18p region is commonly deleted in breast cancer. In this study, we aimed to evaluate PTPN2 protein expression in a large breast cancer cohort, its possible associations to PTPN2 gene copy loss, Akt activation, and the potential use as a clinical marker in breast cancer. Methods PTPN2 protein expression was analysed by immunohistochemistry in 664 node-negative breast tumours from patients enrolled in a randomised tamoxifen trial. DNA was available for 146 patients, PTPN2 gene copy number was determined by real-time PCR. Results PTPN2 gene loss was detected in 17.8% of the tumours. Low PTPN2 protein expression was associated with higher levels of nuclear-activated Akt (pAkt-n). Low PTPN2 as well as the combination variable low PTPN2/high pAkt-n could be used as predictive markers of poor tamoxifen response. Conclusion PTPN2 negatively regulates Akt signalling and loss of PTPN2 protein along with increased pAkt-n is a new potential clinical marker of endocrine treatment efficacy, which may allow for further tailored patient therapies.
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Affiliation(s)
- Elin Karlsson
- Department of Clinical and Experimental Medicine, Department of Oncology, Linköping University, 58185, Linköping, Sweden
| | - Cynthia Veenstra
- Department of Clinical and Experimental Medicine, Department of Oncology, Linköping University, 58185, Linköping, Sweden.
| | - Jon Gårsjö
- Department of Clinical and Experimental Medicine, Department of Oncology, Linköping University, 58185, Linköping, Sweden
| | - Bo Nordenskjöld
- Department of Clinical and Experimental Medicine, Department of Oncology, Linköping University, 58185, Linköping, Sweden
| | - Tommy Fornander
- Department of Oncology, Karolinska University Hospital and Karolinska Institute, 17176, Stockholm, Sweden
| | - Olle Stål
- Department of Clinical and Experimental Medicine, Department of Oncology, Linköping University, 58185, Linköping, Sweden
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Zhang W, Yu W, Cai G, Zhu J, Zhang C, Li S, Guo J, Yin G, Chen C, Kong L. A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy. Cell Death Dis 2018; 9:1098. [PMID: 30368518 PMCID: PMC6204138 DOI: 10.1038/s41419-018-1139-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/03/2018] [Accepted: 10/04/2018] [Indexed: 01/10/2023]
Abstract
Silencing STAT3 is confirmed as a promising therapeutic strategy for triple-negative breast cancer (TNBC) therapy to address the issue of its poor prognosis. In this study, the natural product cryptotanshinone was firstly remodeled and modified as a more effective STAT3 inhibitor by structure-based strategy. The synthetic derivative KYZ3 had 22-24-fold increase in antitumor activity than cryptotanshinone on two TNBC cell lines but had little effect on normal breast epithelial MCF-10A cells. Further investigation showed that KYZ3 inhibited persistent STAT3 phosphorylation. It also prevented the STAT3 protein nuclear translocation to regulate the expressions of the target oncogenes including Bax and Bcl-2. Furthermore, KYZ3 inhibited TNBC cell metastasis by decreasing the levels of MMP-9 which were directly regulated by activated STAT3. A STAT3 plasmid transfecting assay suggested that KYZ3 induced tumor cell apoptosis mainly by targeting STAT3. Finally, KYZ3 suppressed the growth of tumors resulting from subcutaneous implantation of MDA-MB-231 cells in vivo. Taken together, KYZ3 may be a promising cancer therapeutic agent for TNBC.
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Affiliation(s)
- Wenda Zhang
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Wenying Yu
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China.
| | - Guiping Cai
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Jiawen Zhu
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Chao Zhang
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Shanshan Li
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Jianpeng Guo
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Guoping Yin
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Chen Chen
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China
| | - Lingyi Kong
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China.
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Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell 2018; 175:1289-1306.e20. [PMID: 30454647 PMCID: PMC6242467 DOI: 10.1016/j.cell.2018.09.053] [Citation(s) in RCA: 270] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/20/2018] [Accepted: 09/26/2018] [Indexed: 12/12/2022]
Abstract
Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.
Obesity promotes hepatic STAT-1 and STAT-3 signaling Obesity promotes STAT-1-dependent T cell-infiltration, NASH, and fibrosis Obesity promotes NASH-independent STAT-3-dependent HCC
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44
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Protein Tyrosine Phosphatases as Potential Regulators of STAT3 Signaling. Int J Mol Sci 2018; 19:ijms19092708. [PMID: 30208623 PMCID: PMC6164089 DOI: 10.3390/ijms19092708] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/29/2018] [Accepted: 09/06/2018] [Indexed: 02/07/2023] Open
Abstract
The signal transducer and activator of transcription 3 (STAT3) protein is a major transcription factor involved in many cellular processes, such as cell growth and proliferation, differentiation, migration, and cell death or cell apoptosis. It is activated in response to a variety of extracellular stimuli including cytokines and growth factors. The aberrant activation of STAT3 contributes to several human diseases, particularly cancer. Consequently, STAT3-mediated signaling continues to be extensively studied in order to identify potential targets for the development of new and more effective clinical therapeutics. STAT3 activation can be regulated, either positively or negatively, by different posttranslational mechanisms including serine or tyrosine phosphorylation/dephosphorylation, acetylation, or demethylation. One of the major mechanisms that negatively regulates STAT3 activation is dephosphorylation of the tyrosine residue essential for its activation by protein tyrosine phosphatases (PTPs). There are seven PTPs that have been shown to dephosphorylate STAT3 and, thereby, regulate STAT3 signaling: PTP receptor-type D (PTPRD), PTP receptor-type T (PTPRT), PTP receptor-type K (PTPRK), Src homology region 2 (SH-2) domain-containing phosphatase 1(SHP1), SH-2 domain-containing phosphatase 2 (SHP2), MEG2/PTP non-receptor type 9 (PTPN9), and T-cell PTP (TC-PTP)/PTP non-receptor type 2 (PTPN2). These regulators have great potential as targets for the development of more effective therapies against human disease, including cancer.
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45
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Narla G, Sangodkar J, Ryder CB. The impact of phosphatases on proliferative and survival signaling in cancer. Cell Mol Life Sci 2018; 75:2695-2718. [PMID: 29725697 PMCID: PMC6023766 DOI: 10.1007/s00018-018-2826-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 03/24/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023]
Abstract
The dynamic and stringent coordination of kinase and phosphatase activity controls a myriad of physiologic processes. Aberrations that disrupt the balance of this interplay represent the basis of numerous diseases. For a variety of reasons, early work in this area portrayed kinases as the dominant actors in these signaling events with phosphatases playing a secondary role. In oncology, these efforts led to breakthroughs that have dramatically altered the course of certain diseases and directed vast resources toward the development of additional kinase-targeted therapies. Yet, more recent scientific efforts have demonstrated a prominent and sometimes driving role for phosphatases across numerous malignancies. This maturation of the phosphatase field has brought with it the promise of further therapeutic advances in the field of oncology. In this review, we discuss the role of phosphatases in the regulation of cellular proliferation and survival signaling using the examples of the MAPK and PI3K/AKT pathways, c-Myc and the apoptosis machinery. Emphasis is placed on instances where these signaling networks are perturbed by dysregulation of specific phosphatases to favor growth and persistence of human cancer.
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Affiliation(s)
| | - Jaya Sangodkar
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
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46
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Kim M, Baek M, Kim DJ. Protein Tyrosine Signaling and its Potential Therapeutic Implications in Carcinogenesis. Curr Pharm Des 2018. [PMID: 28625132 DOI: 10.2174/1381612823666170616082125] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Protein tyrosine phosphorylation is a crucial signaling mechanism that plays a role in epithelial carcinogenesis. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, metabolism, and motility by activating major signaling pathways including STAT3, AKT, and MAPK. Genetic mutation of PTKs and/or prolonged activation of PTKs and their downstream pathways can lead to the development of epithelial cancer. Therefore, PTKs became an attractive target for cancer prevention. PTK inhibitors are continuously being developed, and they are currently used for the treatment of cancers that show a high expression of PTKs. Protein tyrosine phosphatases (PTPs), the homeostatic counterpart of PTKs, negatively regulate the rate and duration of phosphotyrosine signaling. PTPs initially were considered to be only housekeeping enzymes with low specificity. However, recent studies have demonstrated that PTPs can function as either tumor suppressors or tumor promoters, depending on their target substrates. Together, both PTK and PTP signal transduction pathways are potential therapeutic targets for cancer prevention and treatment.
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Affiliation(s)
- Mihwa Kim
- Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Minwoo Baek
- Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
| | - Dae Joon Kim
- Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA
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47
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Zhang P, Zhang W, Zhang D, Wang M, Aprecio R, Ji N, Mohamed O, Li Y, Ding Y, Wang Q. 25-Hydroxyvitamin D 3 -enhanced PTPN2 positively regulates periodontal inflammation through the JAK/STAT pathway in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. J Periodontal Res 2018. [PMID: 29516520 DOI: 10.1111/jre.12535] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE Periodontitis is an increasingly prevalent complication of diabetes mellitus (known as diabetes mellitus-associated periodontitis), and 25-hydroxyvitamin D3 (25VD3 ) was recently found to be a critical regulator of innate immunity in this disease, but the underlying mechanisms remain poorly understood. T-cell protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a potential downstream protein of the 25VD3 /vitamin D receptor pathway. The aim of this study was to investigate the regulation of PTPN2 in periodontal inflammation in diabetes mellitus-associated periodontitis. MATERIAL AND METHODS Porphyromonas gingivalis-infected db/db mice were treated with 25VD3 . Their fasting blood glucose and body weight were monitored every other week, and the levels of alveolar bone loss and serum inflammatory cytokines (tumor necrosis factor-α, interferon-γ and interleukin-6) were determined at the time of killing. The effect of PTPN2 on human OKF6-TERT2 oral keratinocytes was examined through the knockout of PTPN2 using the CRISPR/Cas9 knockout plasmid. The expression levels of the PTPN2, vitamin D receptor and JAK1/STAT3 signaling proteins in the gingival epithelium and OKF6-TERT2 cells were determined through western blot and immunohistochemical analyses. RESULTS After 25VD3 treatment, db/db mice exhibited alleviated serum inflammatory cytokines and alveolar bone loss, and 25VD3 -enhanced PTPN2 expression decreased the expression of the JAK1/STAT3 signaling proteins in the gingival epithelium. Analyses of human oral keratinocytes showed that 25VD3 increased the expression of PTPN2, which dephosphorylates protein substrates in the JAK1/STAT3 signaling pathway. CONCLUSION PTPN2 contributed to a decrease in periodontal inflammation in type 2 diabetes mellitus via dephosphorylate protein substrates in the JAK1/STAT3 signaling pathway after 25VD3 treatment in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. A thorough understanding of PTPN2 and its involvement in inhibiting inflammation might provide alternative therapeutic approaches for the pathogenesis and treatment of diabetes mellitus-associated periodontitis.
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Affiliation(s)
- P Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - W Zhang
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - D Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China
| | - M Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - R Aprecio
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - N Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - O Mohamed
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - Y Li
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - Y Ding
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Q Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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48
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Chalakur-Ramireddy NKR, Pakala SB. Combined drug therapeutic strategies for the effective treatment of Triple Negative Breast Cancer. Biosci Rep 2018; 38:BSR20171357. [PMID: 29298879 PMCID: PMC5789156 DOI: 10.1042/bsr20171357] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/12/2017] [Accepted: 01/01/2018] [Indexed: 12/19/2022] Open
Abstract
TNBC (Triple Negative Breast Cancer) is a subtype of breast cancer with an aggressive phenotype which shows high metastatic capability and poor prognosis. Owing to its intrinsic properties like heterogeneity, lack of hormonal receptors and aggressive phenotype leave chemotherapy as a mainstay for the treatment of TNBC. Various studies have demonstrated that chemotherapy alone or therapeutic drugs targeting TNBC pathways, epigenetic mechanisms and immunotherapy alone have not shown significant improvement in TNBC patients. On the other hand, a combination of therapeutic drugs or addition of chemotherapy with therapeutic drugs has shown substantial improvement in results and proven to be an effective strategy for TNBC treatment. This review sheds light on effective combinational drug strategies and current clinical trial status of various combinatorial drugs for the treatment of TNBC.
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Affiliation(s)
| | - Suresh B Pakala
- Biology Division, Indian Institute of Science Education and Research (IISER) Tirupati, Andhra Pradesh, India
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49
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Khan MW, Saadalla A, Ewida AH, Al-Katranji K, Al-Saoudi G, Giaccone ZT, Gounari F, Zhang M, Frank DA, Khazaie K. The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol Immunother 2018; 67:13-23. [PMID: 28875329 PMCID: PMC5783191 DOI: 10.1007/s00262-017-2057-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 08/29/2017] [Indexed: 12/29/2022]
Abstract
The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8+ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.
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Affiliation(s)
- Mohammad W Khan
- Department of Biology, San Diego State University, 5500 Campanile Drive, NLS-407, San Diego, CA, 92182, USA
| | - Abdulrahman Saadalla
- Department of Immunology, Department of Surgery, Mayo Clinic, Guggenheim 3-42B, Rochester, MN, 55905, USA
| | - Ahmed H Ewida
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior Street, Lurie 3-250, Chicago, IL, 60611, USA
| | - Khalid Al-Katranji
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior Street, Lurie 3-250, Chicago, IL, 60611, USA
| | - Ghadier Al-Saoudi
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior Street, Lurie 3-250, Chicago, IL, 60611, USA
| | - Zachary T Giaccone
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Fotini Gounari
- Department of Medicine, Section of Rheumatology, University of Chicago, JFK R314, 924 East 57th Street, MC 0930, Chicago, IL, 60637, USA
| | - Ming Zhang
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior Street, Lurie 3-250, Chicago, IL, 60611, USA
- Departments of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - David A Frank
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Khashayarsha Khazaie
- Department of Immunology, Department of Surgery, Mayo Clinic, Guggenheim 3-42B, Rochester, MN, 55905, USA.
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50
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Meeusen B, Janssens V. Tumor suppressive protein phosphatases in human cancer: Emerging targets for therapeutic intervention and tumor stratification. Int J Biochem Cell Biol 2017; 96:98-134. [PMID: 29031806 DOI: 10.1016/j.biocel.2017.10.002] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 10/04/2017] [Accepted: 10/05/2017] [Indexed: 02/06/2023]
Abstract
Aberrant protein phosphorylation is one of the hallmarks of cancer cells, and in many cases a prerequisite to sustain tumor development and progression. Like protein kinases, protein phosphatases are key regulators of cell signaling. However, their contribution to aberrant signaling in cancer cells is overall less well appreciated, and therefore, their clinical potential remains largely unexploited. In this review, we provide an overview of tumor suppressive protein phosphatases in human cancer. Along their mechanisms of inactivation in defined cancer contexts, we give an overview of their functional roles in diverse signaling pathways that contribute to their tumor suppressive abilities. Finally, we discuss their emerging roles as predictive or prognostic markers, their potential as synthetic lethality targets, and the current feasibility of their reactivation with pharmacologic compounds as promising new cancer therapies. We conclude that their inclusion in clinical practice has obvious potential to significantly improve therapeutic outcome in various ways, and should now definitely be pushed forward.
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Affiliation(s)
- Bob Meeusen
- Laboratory of Protein Phosphorylation & Proteomics, Dept. of Cellular & Molecular Medicine, Faculty of Medicine, KU Leuven & Leuven Cancer Institute (LKI), KU Leuven, Belgium
| | - Veerle Janssens
- Laboratory of Protein Phosphorylation & Proteomics, Dept. of Cellular & Molecular Medicine, Faculty of Medicine, KU Leuven & Leuven Cancer Institute (LKI), KU Leuven, Belgium.
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