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1
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Kao WH, Chiu KY, Tsai SCS, Teng CLJ, Oner M, Lai CH, Hsieh JT, Lin CC, Wang HY, Chen MC, Lin H. PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167568. [PMID: 39536992 DOI: 10.1016/j.bbadis.2024.167568] [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: 04/01/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Aberrant PI3K/Akt activation is linked to prostate cancer (PCa) malignancy, while androgen receptor (AR) is critical in early-stage PCa development. Investigating the interaction between these pathways is crucial for PCa malignancy. Our previous study demonstrated that p35-CDK5 mediates post-translational modifications of AR, STAT3, and p21CIP1, eventually promoting PCa cell growth. This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the β-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.
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Affiliation(s)
- Wei-Hsiang Kao
- Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan; Translational Cell Therapy Center, China Medical University Hospital, Taichung 40447, Taiwan.
| | - Kun-Yuan Chiu
- Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan
| | - Stella Chin-Shaw Tsai
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan; Superintendent Office, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan; College of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan
| | - Chieh-Lin Jerry Teng
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan; Division of Hematology/Medical Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
| | - Muhammet Oner
- Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
| | - Chih-Ho Lai
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan 33302, Taiwan.
| | - Jer-Tsong Hsieh
- Department of Urology, University of Texas Southwestern Medical Center, TX75390, USA.
| | - Chi-Chien Lin
- Institute of Biomedical Science, National Chung Hsing University, Taichung 40227, Taiwan
| | - Hsin-Yi Wang
- Department of Nuclear Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
| | - Mei-Chih Chen
- Translational Cell Therapy Center, China Medical University Hospital, Taichung 40447, Taiwan.
| | - Ho Lin
- Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
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2
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Wang J, Zhang C, Jiang T, He Y, Wu Y, Zhou D, Yan J, Zhou Y. CDK5: Insights into its roles in diseases. Mol Biol Rep 2025; 52:145. [PMID: 39836243 DOI: 10.1007/s11033-025-10253-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
Cyclin-dependent kinase 5 (CDK5), a unique member of the CDK family, is a proline-directed serine/threonine protein kinase with critical roles in various physiological and pathological processes. Widely expressed in the central nervous system, CDK5 is strongly implicated in neurological diseases. Beyond its neurological roles, CDK5 is involved in metabolic disorders, psychiatric conditions, and tumor progression, contributing to processes such as proliferation, migration, immune evasion, genomic stability, and angiogenesis. This review explores the structure and biological functions of CDK5, highlighting its regulatory roles in disease development through the phosphorylation of diverse substrate proteins. Additionally, we examine the therapeutic potential of CDK5 inhibition, offering novel perspectives for disease diagnosis and treatment.
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Affiliation(s)
- Jiahui Wang
- Institute of Pathogenic Biology, Guilin Medical University, Guilin, 541199, China
| | - Chong Zhang
- Department of Neurology, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
- Guangxi Medical and Health Key Cultivation Discipline Construction Project, Guilin, 541199, China
| | - Tingting Jiang
- Institute of Pathogenic Biology, Guilin Medical University, Guilin, 541199, China
| | - Yi He
- Institute of Pathogenic Biology, Guilin Medical University, Guilin, 541199, China
| | - Yongli Wu
- Institute of Pathogenic Biology, Guilin Medical University, Guilin, 541199, China
| | - Dongsheng Zhou
- Guangxi Medical and Health Key Cultivation Discipline Construction Project, Guilin, 541199, China
- Department of Infectious Diseases, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| | - Jianguo Yan
- Guangxi Medical and Health Key Cultivation Discipline Construction Project, Guilin, 541199, China.
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, 541199, China.
- Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, 541199, China.
| | - Yali Zhou
- Institute of Pathogenic Biology, Guilin Medical University, Guilin, 541199, China.
- Guangxi Medical and Health Key Cultivation Discipline Construction Project, Guilin, 541199, China.
- Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, 541199, China.
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3
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Pellarin I, Dall'Acqua A, Favero A, Segatto I, Rossi V, Crestan N, Karimbayli J, Belletti B, Baldassarre G. Cyclin-dependent protein kinases and cell cycle regulation in biology and disease. Signal Transduct Target Ther 2025; 10:11. [PMID: 39800748 PMCID: PMC11734941 DOI: 10.1038/s41392-024-02080-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/16/2024] [Accepted: 11/13/2024] [Indexed: 01/18/2025] Open
Abstract
Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions. Here, we describe the functions of CDKs, categorized into the three main functional groups in which they are classified, highlighting the most relevant pathways that drive their expression and functions. We then discuss the potential roles and deregulation of CDKs in human pathologies, with a particular focus on cancer, the human disease in which CDKs have been most extensively studied and explored as therapeutic targets. Finally, we discuss how CDKs inhibitors have become standard therapies in selected human cancers and propose novel ways of investigation to export their targeting from cancer to other relevant chronic diseases. We hope that the effort we made in collecting all available information on both the prominent and lesser-known CDK family members will help in identify and develop novel areas of research to improve the lives of patients affected by debilitating chronic diseases.
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Affiliation(s)
- Ilenia Pellarin
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Alessandra Dall'Acqua
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Andrea Favero
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Ilenia Segatto
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Valentina Rossi
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Nicole Crestan
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Javad Karimbayli
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Barbara Belletti
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy
| | - Gustavo Baldassarre
- Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy.
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4
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Yuzhalin AE, Lowery FJ, Saito Y, Yuan X, Yao J, Duan Y, Ding J, Acharya S, Zhang C, Fajardo A, Chen HN, Wei Y, Sun Y, Zhang L, Xiao Y, Li P, Lorenzi PL, Huse JT, Fan H, Zhao Z, Hung MC, Yu D. Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition. Nat Cell Biol 2024; 26:1773-1789. [PMID: 39304713 PMCID: PMC11676029 DOI: 10.1038/s41556-024-01509-5] [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: 07/03/2023] [Accepted: 08/16/2024] [Indexed: 09/22/2024]
Abstract
Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.
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Affiliation(s)
- Arseniy E Yuzhalin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Frank J Lowery
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yohei Saito
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiangliang Yuan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jun Yao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yimin Duan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jingzhen Ding
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sunil Acharya
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chenyu Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abigail Fajardo
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hao-Nien Chen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yongkun Wei
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lin Zhang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yi Xiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ping Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Philip L Lorenzi
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jason T Huse
- Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Huihui Fan
- Center for Precision Health, McWilliams School of Biomedical Informatics, Houston, TX, USA
- John P and Katherine G McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zhongming Zhao
- Center for Precision Health, McWilliams School of Biomedical Informatics, Houston, TX, USA
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung City, Taiwan
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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5
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Nikhil K, Shah K. CDK5: an oncogene or an anti-oncogene: location location location. Mol Cancer 2023; 22:186. [PMID: 37993880 PMCID: PMC10666462 DOI: 10.1186/s12943-023-01895-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/03/2023] [Indexed: 11/24/2023] Open
Abstract
Recent studies have uncovered various physiological functions of CDK5 in many nonneuronal tissues. Upregulation of CDK5 and/or its activator p35 in neurons promotes healthy neuronal functions, but their overexpression in nonneuronal tissues is causally linked to cancer of many origins. This review focuses on the molecular mechanisms by which CDK5 recruits diverse tissue-specific substrates to elicit distinct phenotypes in sixteen different human cancers. The emerging theme suggests that CDK5's role as an oncogene or anti-oncogene depends upon its subcellular localization. CDK5 mostly acts as an oncogene, but in gastric cancer, it is a tumor suppressor due to its unique nuclear localization. This indicates that CDK5's access to certain nuclear substrates converts it into an anti-oncogenic kinase. While acting as a bonafide oncogene, CDK5 also activates a few cancer-suppressive pathways in some cancers, presumably due to the mislocalization of nuclear substrates in the cytoplasm. Therefore, directing CDK5 to the nucleus or exporting tumor-suppressive nuclear substrates to the cytoplasm may be promising approaches to combat CDK5-induced oncogenicity, analogous to neurotoxicity triggered by nuclear CDK5. Furthermore, while p35 overexpression is oncogenic, hyperactivation of CDK5 by inducing p25 formation results in apoptosis, which could be exploited to selectively kill cancer cells by dialing up CDK5 activity, instead of inhibiting it. CDK5 thus acts as a molecular rheostat, with different activity levels eliciting distinct functional outcomes. Finally, as CDK5's role is defined by its substrates, targeting them individually or in conjunction with CDK5 should create potentially valuable new clinical opportunities.
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Affiliation(s)
- Kumar Nikhil
- Department of Chemistry, Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN, 47907, USA
- School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, 751024, India
| | - Kavita Shah
- Department of Chemistry, Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN, 47907, USA.
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6
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Maharati A, Moghbeli M. Long non-coding RNAs as the critical regulators of PI3K/AKT, TGF-β, and MAPK signaling pathways during breast tumor progression. J Transl Med 2023; 21:556. [PMID: 37596669 PMCID: PMC10439650 DOI: 10.1186/s12967-023-04434-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/11/2023] [Indexed: 08/20/2023] Open
Abstract
Breast cancer (BC) as one of the most common causes of human deaths among women, is always considered one of the global health challenges. Despite various advances in diagnostic and therapeutic methods, a significant percentage of BC patients have a poor prognosis due to the lack of therapeutic response. Therefore, investigating the molecular mechanisms involved in BC progression can improve the therapeutic and diagnostic strategies in these patients. Cytokine and growth factor-dependent signaling pathways play a key role during BC progression. In addition to cytokines and growth factors, long non-coding RNAs (lncRNAs) have also important roles in regulation of such signaling pathways. Therefore, in the present review we discussed the role of lncRNAs in regulation of PI3K/AKT, MAPK, and TGF-β signaling pathways in breast tumor cells. It has been shown that lncRNAs mainly have an oncogenic role through the promotion of these signaling pathways in BC. This review can be an effective step in introducing the lncRNAs inhibition as a probable therapeutic strategy to reduce tumor growth by suppression of PI3K/AKT, MAPK, and TGF-β signaling pathways in BC patients. In addition, considering the oncogenic role and increased levels of lncRNAs expressions in majority of the breast tumors, lncRNAs can be also considered as the reliable diagnostic markers in BC patients.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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7
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Jabeur R, Corbel C, Loyer P, Le Parc A, Le Grand A, Comte A, Bach S, André-Leroux G, Sire O, Ben Mansour H, Le Tilly V. Identification of Novel Compounds Inhibiting the Kinase Activity of the CDK5/p25 Complex via Direct Binding to p25. Biochemistry 2023; 62:1452-1463. [PMID: 37074084 DOI: 10.1021/acs.biochem.2c00691] [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] [Indexed: 04/20/2023]
Abstract
Tamoxifen, the gold standard drug for endocrine therapy for breast cancer, modulates the phosphorylation status of the TAU protein in Alzheimer's disease by inhibiting CDK5 kinase activity. Its binding to p25 prevents CDK5/p25 complexation and hence a decrease of CDK5 activity. In breast tumors, this complex is involved in the proliferation and survival of cancer cells, as well as in the disease's prognosis. Still, the molecular stability of the CDK5/p25 complex following tamoxifen exposure in this cancer type has not yet been clearly deciphered. Here, we report the functional characterization of CDK5 and its p25 regulatory subunit in the absence and presence of tamoxifen. In addition, two novel inhibitors of the kinase activity of the CDK5/p25 complex are identified, both of which would reduce the risk of recurrence of estrogen receptor-positive (ER+) breast cancers and prevent drawbacks induced by tamoxifen exposure. Accordingly, 6His-CDK5 and 6His-p25 have been expressed and purified. Fluorescence anisotropy measurements have been used to assess that the two proteins do form an active complex, and thermodynamic parameters of their interaction were measured. It was also confirmed that tamoxifen directly binds to p25 and inhibits CDK5 kinase activity. Similar observations were obtained using 4-hydroxytamoxifen, an active metabolized form of tamoxifen. Two novel compounds have been identified here that harbor a benzofuran moiety and were shown to target directly p25, and their bindings resulted in decreased CDK5 kinase activity. This encouraging alternative opens the way to the ensuing chemical optimization of this scaffold. It also promises a more specific therapeutic approach that may both tackle the pathological signaling in breast cancer and provide a potential new drug for Alzheimer's disease.
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Affiliation(s)
- Riheb Jabeur
- IRDL UMR CNRS 6027, Université Bretagne Sud, 56017 Vannes, France
- Research Unit of Analysis and Process Applied on the Environment─APAE UR17ES32, Higher Institute of Applied Sciences and Technology, Mahdia, University of Monastir, TN5121 Monastir, Tunisia
| | - Caroline Corbel
- IRDL UMR CNRS 6027, Université Bretagne Sud, 56017 Vannes, France
| | - Pascal Loyer
- Univ Rennes, INSERM, INRAE, Institut NuMeCan (Nutrition, Metabolisms and Cancer) UMR-A 1341, UMR-S 1241, F-35000 Rennes, France
| | | | | | - Arnaud Comte
- Compound Library, ICBMS UMR 5246 CNRS-Université Claude Bernard Lyon 1, Université de Lyon, 69622 Villeurbanne, France
| | - Stéphane Bach
- Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France
- Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, 29680 Roscoff, France
- Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, 2520 Potchefstroom, South Africa
| | | | - Olivier Sire
- IRDL UMR CNRS 6027, Université Bretagne Sud, 56017 Vannes, France
| | - Hedi Ben Mansour
- Research Unit of Analysis and Process Applied on the Environment─APAE UR17ES32, Higher Institute of Applied Sciences and Technology, Mahdia, University of Monastir, TN5121 Monastir, Tunisia
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8
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Wong DP, Fritz CE, Feinberg D, Huang AY, Parameswaran R. p35 is a Crucial Player in NK-cell Cytotoxicity and TGFβ-mediated NK-cell Dysfunction. CANCER RESEARCH COMMUNICATIONS 2023; 3:793-806. [PMID: 37377891 PMCID: PMC10162136 DOI: 10.1158/2767-9764.crc-22-0497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/14/2023] [Accepted: 04/14/2023] [Indexed: 06/29/2023]
Abstract
Natural killer (NK) cells are innate lymphocytes with cytotoxic activity. Understanding the factors regulating cytotoxicity is crucial for improving NK-cell adoptive therapies. Here, we studied a previously unknown role of p35 (CDK5R1), a coactivator of cyclin-dependent kinase 5 (CDK5) in NK-cell function. p35 expression was thought to be neuronal-specific and the majority of studies are still focused on neuronal cells. Here, we show that CDK5 and p35 are expressed in NK cells and are kinase-active. NK cells from p35 knockout mice were analyzed and showed significantly increased cytotoxicity against murine cancer cells, while they did not show any differences in cell numbers or maturation stages. We confirmed this using human NK cells transduced with p35 short hairpin RNA (shRNA), showing similar increase in cytotoxicity against human cancer cells. Overexpression of p35 in NK cells resulted in moderate decrease in cytotoxicity, while expressing a kinase-dead mutant of CDK5 displayed increased cytotoxicity. Together, these data suggest that p35 negatively regulates NK-cell cytotoxicity. Surprisingly, we found that TGFβ, a known negative regulator of NK-cell cytotoxicity, induces p35 expression in NK cells. NK cells cultured with TGFβ exhibit reduced cytotoxicity, while NK cells transduced with p35 shRNA or mutant CDK5 expression exhibited partial reversal of this inhibitory effect pointing to an interesting hypothesis that p35 plays an important role in TGFβ-mediated NK-cell exhaustion. Significance This study reports a role for p35 in NK-cell cytotoxicity and this might help to improve NK-cell adoptive therapy.
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Affiliation(s)
- Derek P. Wong
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Claire E. Fritz
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Daniel Feinberg
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Alex Y. Huang
- Pediatric Hematology and Oncology, The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, Ohio
- The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Reshmi Parameswaran
- The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
- Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
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9
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Zabihi M, Lotfi R, Yousefi AM, Bashash D. Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities. J Cancer Res Clin Oncol 2023; 149:1585-1606. [PMID: 35781526 DOI: 10.1007/s00432-022-04135-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/13/2022] [Indexed: 12/20/2022]
Abstract
The discussion on cell proliferation cannot be continued without taking a look at the cell cycle regulatory machinery. Cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs) are valuable members of this system and their equilibrium guarantees the proper progression of the cell cycle. As expected, any dysregulation in the expression or function of these components can provide a platform for excessive cell proliferation leading to tumorigenesis. The high frequency of CDK abnormalities in human cancers, together with their druggable structure has raised the possibility that perhaps designing a series of inhibitors targeting CDKs might be advantageous for restricting the survival of tumor cells; however, their application has faced a serious concern, since these groups of serine-threonine kinases possess non-canonical functions as well. In the present review, we aimed to take a look at the biology of CDKs and then magnify their contribution to tumorigenesis. Then, by arguing the bright and dark aspects of CDK inhibition in the treatment of human cancers, we intend to reach a consensus on the application of these inhibitors in clinical settings.
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Affiliation(s)
- Mitra Zabihi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramin Lotfi
- Clinical Research Development Center, Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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10
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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11
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ß-Adrenoreceptors in Human Cancers. Int J Mol Sci 2023; 24:ijms24043671. [PMID: 36835082 PMCID: PMC9964924 DOI: 10.3390/ijms24043671] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/04/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
Cancer is the leading cause of death and represents a significant economic burden worldwide. The numbers are constantly growing as a result of increasing life expectancy, toxic environmental factors, and adoption of Western lifestyle. Among lifestyle factors, stress and the related signaling pathways have recently been implicated in the development of tumors. Here we present some epidemiological and preclinical data concerning stress-related activation of the ß-adrenoreceptors (ß-ARs), which contributes to the formation, sequential transformation, and migration of different tumor cell types. We focused our survey on research results for breast and lung cancer, melanoma, and gliomas published in the past five years. Based on the converging evidence, we present a conceptual framework of how cancer cells hijack a physiological mechanism involving ß-ARs toward a positive modulation of their own survival. In addition, we also highlight the potential contribution of ß-AR activation to tumorigenesis and metastasis formation. Finally, we outline the antitumor effects of targeting the ß-adrenergic signaling pathways, methods for which primarily include repurposed ß-blocker drugs. However, we also call attention to the emerging (though as yet largely explorative) method of chemogenetics, which has a great potential in suppressing tumor growth either by selectively modulating neuronal cell groups involved in stress responses affecting cancer cells or by directly manipulating specific (e.g., the ß-AR) receptors on a tumor and its microenvironment.
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12
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Liu Y, Han J, Kong T, Xiao N, Mei Q, Liu J. DriverMP enables improved identification of cancer driver genes. Gigascience 2022; 12:giad106. [PMID: 38091511 PMCID: PMC10716827 DOI: 10.1093/gigascience/giad106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/30/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Cancer is widely regarded as a complex disease primarily driven by genetic mutations. A critical concern and significant obstacle lies in discerning driver genes amid an extensive array of passenger genes. FINDINGS We present a new method termed DriverMP for effectively prioritizing altered genes on a cancer-type level by considering mutated gene pairs. It is designed to first apply nonsilent somatic mutation data, protein‒protein interaction network data, and differential gene expression data to prioritize mutated gene pairs, and then individual mutated genes are prioritized based on prioritized mutated gene pairs. Application of this method in 10 cancer datasets from The Cancer Genome Atlas demonstrated its great improvements over all the compared state-of-the-art methods in identifying known driver genes. Then, a comprehensive analysis demonstrated the reliability of the novel driver genes that are strongly supported by clinical experiments, disease enrichment, or biological pathway analysis. CONCLUSIONS The new method, DriverMP, which is able to identify driver genes by effectively integrating the advantages of multiple kinds of cancer data, is available at https://github.com/LiuYangyangSDU/DriverMP. In addition, we have developed a novel driver gene database for 10 cancer types and an online service that can be freely accessed without registration for users. The DriverMP method, the database of novel drivers, and the user-friendly online server are expected to contribute to new diagnostic and therapeutic opportunities for cancers.
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Affiliation(s)
- Yangyang Liu
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Jiyun Han
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Tongxin Kong
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Nannan Xiao
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
| | - Qinglin Mei
- MOE Key Laboratory of Bioinformatics, BNRIST Bioinformatics Division, Department of Automation, Tsinghua University, Beijing 100084, China
| | - Juntao Liu
- School of Mathematics and Statistics, Shandong University (Weihai), Weihai 264209, China
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13
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Taguchi K, Elias BC, Sugahara S, Sant S, Freedman BS, Waikar SS, Pozzi A, Zent R, Harris RC, Parikh SM, Brooks CR. Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation. J Clin Invest 2022; 132:e158096. [PMID: 36453545 PMCID: PMC9711881 DOI: 10.1172/jci158096] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 10/05/2022] [Indexed: 12/02/2022] Open
Abstract
Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and predisposes patients to chronic kidney disease (CKD) through the AKI-to-CKD transition. Studies from our laboratory and others have demonstrated that maladaptive repair of proximal tubule cells (PTCs), including induction of dedifferentiation, G2/M cell cycle arrest, senescence, and profibrotic cytokine secretion, is a key process promoting AKI-to-CKD transition, kidney fibrosis, and CKD progression. The molecular mechanisms governing maladaptive repair and the relative contribution of dedifferentiation, G2/M arrest, and senescence to CKD remain to be resolved. We identified cyclin G1 (CG1) as a factor upregulated in chronically injured and maladaptively repaired PTCs. We demonstrated that global deletion of CG1 inhibits G2/M arrest and fibrosis. Pharmacological induction of G2/M arrest in CG1-knockout mice, however, did not fully reverse the antifibrotic phenotype. Knockout of CG1 did not alter dedifferentiation and proliferation in the adaptive repair response following AKI. Instead, CG1 specifically promoted the prolonged dedifferentiation of kidney tubule epithelial cells observed in CKD. Mechanistically, CG1 promotes dedifferentiation through activation of cyclin-dependent kinase 5 (CDK5). Deletion of CDK5 in kidney tubule cells did not prevent G2/M arrest but did inhibit dedifferentiation and fibrosis. Thus, CG1 and CDK5 represent a unique pathway that regulates maladaptive, but not adaptive, dedifferentiation, suggesting they could be therapeutic targets for CKD.
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Affiliation(s)
- Kensei Taguchi
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Bertha C. Elias
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sho Sugahara
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Snehal Sant
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Benjamin S. Freedman
- Kidney Research Institute, Institute for Stem Cell and Regenerative Medicine, and Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Sushrut S. Waikar
- Section of Nephrology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Ambra Pozzi
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Hospital, Nashville, Tennessee, USA
| | - Roy Zent
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Hospital, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Raymond C. Harris
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Hospital, Nashville, Tennessee, USA
| | - Samir M. Parikh
- Division of Nephrology, Department of Internal Medicine, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Craig R. Brooks
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
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14
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Machine Learning-Based Virtual Screening for the Identification of Cdk5 Inhibitors. Int J Mol Sci 2022; 23:ijms231810653. [PMID: 36142566 PMCID: PMC9502400 DOI: 10.3390/ijms231810653] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 12/04/2022] Open
Abstract
Cyclin-dependent kinase 5 (Cdk5) is an atypical proline-directed serine/threonine protein kinase well-characterized for its role in the central nervous system rather than in the cell cycle. Indeed, its dysregulation has been strongly implicated in the progression of synaptic dysfunction and neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also in the development and progression of a variety of cancers. For this reason, Cdk5 is considered as a promising target for drug design, and the discovery of novel small-molecule Cdk5 inhibitors is of great interest in the medicinal chemistry field. In this context, we employed a machine learning-based virtual screening protocol with subsequent molecular docking, molecular dynamics simulations and binding free energy evaluations. Our virtual screening studies resulted in the identification of two novel Cdk5 inhibitors, highlighting an experimental hit rate of 50% and thus validating the reliability of the in silico workflow. Both identified ligands, compounds CPD1 and CPD4, showed a promising enzyme inhibitory activity and CPD1 also demonstrated a remarkable antiproliferative activity in ovarian and colon cancer cells. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent Cdk5 inhibitors.
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15
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Activity of ROCKII not ROCKI promotes pulmonary metastasis of melanoma cells via modulating Smad2/3-MMP9 and FAK-Src-VEGF signalling. Cell Signal 2022; 97:110389. [PMID: 35718242 DOI: 10.1016/j.cellsig.2022.110389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/03/2022] [Accepted: 06/13/2022] [Indexed: 11/20/2022]
Abstract
Rho-associated coiled-coil kinase (ROCK) inhibition decreases tumourogenic growth, proliferation and angiogenesis. Multifaceted evidences are there about the role of ROCK in cancer progression, but isoform specific analysis in secondary pulmonary melanoma is still unaddressed. This study explored the operating function of ROCK in the metastasis of B16F10 mice melanoma cell line. Inhibition by KD-025 indicated dual wielding role of ROCKII as it is associated with the regulation of MMP9 activity responsible for extra-cellular matrix (ECM) degradation as well as angiogenic invasion as an effect of Src-FAK-STAT3 interaction dependent VEGF switching. We found the assisting role of ROCKII, not ROCKI in nuclear localization of Smads that effectively increased MMP9 expression and activity (p < 0.01). This cleaved the protein components of ECM thereby played a crucial role in tissue remodeling at secondary site during establishment of metastatic tumour. ROCKII phosphorylation at Ser1366 as an activation of the same was imprinted essential for oncogenic molecular bagatelle leading to histo-architectural change of pulmonary tissue with extracellular matrix degradation as a consequence of invasion. Direct correlation of pROCKIISer1366 with MMP9 as well as VEGF expression in vivo studies cue to demonstrate the importance of pROCKIISer1366 inhibition in the context of angiogenesis, and metastasis suggesting ROCKII signaling as a possible target for the treatment of secondary lung cancer specially in metastatic melanoma.
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16
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Silva D, Quintas C, Gonçalves J, Fresco P. Contribution of adrenergic mechanisms for the stress-induced breast cancer carcinogenesis. J Cell Physiol 2022; 237:2107-2127. [PMID: 35243626 DOI: 10.1002/jcp.30707] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/21/2022] [Accepted: 02/12/2022] [Indexed: 12/11/2022]
Abstract
Breast cancer is the most common and deadliest type of cancer in women. Stress exposure has been associated with carcinogenesis and the stress released neurotransmitters, noradrenaline and adrenaline, and their cognate receptors, can participate in the carcinogenesis process, either by regulating tumor microenvironment or by promoting systemic changes. This work intends to provide an overview of the research done in this area and try to unravel the role of adrenergic ligands in the context of breast carcinogenesis. In the initiation phase, adrenergic signaling may favor neoplastic transformation of breast epithelial cells whereas, during cancer progression, may favor the metastatic potential of breast cancer cells. Additionally, adrenergic signaling can alter the function and activity of other cells present in the tumor microenvironment towards a protumor phenotype, namely macrophages, fibroblasts, and by altering adipocyte's function. Adrenergic signaling also promotes angiogenesis and lymphangiogenesis and, systemically, may induce the formation of preneoplastic niches, cancer-associated cachexia and alterations in the immune system which contribute for the loss of quality of life of breast cancer patients and their capacity to fight cancer. Most studies points to a major contribution of β2 -adrenoceptor activated pathways on these effects. The current knowledge of the mechanistic pathways activated by β2 -adrenoceptors in physiology and pathophysiology, the availability of selective drugs approved for clinical use and a deeper knowledge of the basic cellular and molecular pathways by which adrenergic stimulation may influence cancer initiation and progression, opens the possibility to use new therapeutic alternatives to improve efficacy of breast cancer treatments.
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Affiliation(s)
- Dany Silva
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Clara Quintas
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Jorge Gonçalves
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Paula Fresco
- Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
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17
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Wu ZH, Yang DL, Wang L, Liu J. Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma. Front Immunol 2021; 12:793343. [PMID: 34925377 PMCID: PMC8674919 DOI: 10.3389/fimmu.2021.793343] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/17/2021] [Indexed: 01/02/2023] Open
Abstract
Background Epigenetics regulate gene expression without altering the DNA sequence. Epigenetics targeted chemotherapeutic approach can be used to overcome treatment resistance and low response rate in HCC. However, a comprehensive review of genomic data was carried out to determine the role of epigenesis in the tumor microenvironment (TME), immune cell-infiltration characteristics in HCC is still insufficient. Methods The association between epigenetic-related genes (ERGs), inflammatory response-related genes (IRRGs) and CRISPR genes was determined by merging genomic and CRISPR data. Further, characteristics of immune-cell infiltration in the tumor microenvironment was evaluated. Results Nine differentially expressed genes (ANP32B, ASF1A, BCORL1, BMI1, BUB1, CBX2, CBX3, CDK1, and CDK5) were shown to be independent prognostic factors based on lasso regression in the TCGA-LIHC and ICGC databases. In addition, the results showed significant differences in expression of PDCD-1 (PD-1) and CTLA4 between the high- and low-epigenetic score groups. The CTRP and PRISM-derived drug response data yielded four CTRP-derived compounds (SB-743921, GSK461364, gemcitabine, and paclitaxel) and two PRISM-derived compounds (dolastatin-10 and LY2606368). Patients with high ERGs benefited more from immune checkpoint inhibitor (ICI) therapy than patients with low ERGs. In addition, the high ERGs subgroup had a higher T cell exclusion score, while the low ERGs subgroup had a higher T cell dysfunction. However, there was no difference in microsatellite instability (MSI) score among the two subgroups. Further, genome-wide CRISPR-based loss-of function screening derived from DepMap was conducted to determine key genes leading to HCC development and progression. In total, 640 genes were identified to be essential for survival in HCC cell lines. The protein-protein interaction (PPI) network demonstrated that IRRGs PSEN1 was linked to most ERGs and CRISPR genes such as CDK1, TOP2A, CBX2 and CBX3. Conclusion Epigenetic alterations of cancer-related genes in the tumor microenvironment play a major role in carcinogenesis. This study showed that epigenetic-related novel biomarkers could be useful in predicting prognosis, clinical diagnosis, and management in HCC.
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Affiliation(s)
- Zeng-Hong Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong-Liang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liang Wang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Sui R, Shi W, Han S, Fan X, Zhang X, Wang N, Zhang H, Xu A, Liu C. MiR-142-5p directly targets cyclin-dependent kinase 5-mediated upregulation of the inflammatory process in acquired middle ear cholesteatoma. Mol Immunol 2021; 141:236-245. [PMID: 34875451 DOI: 10.1016/j.molimm.2021.11.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 10/20/2021] [Accepted: 11/22/2021] [Indexed: 01/27/2023]
Abstract
MicroRNAs (miRNAs) play important roles in the regulation of cell proliferation, differentiation, apoptosis, and inflammatory responses. MiR-142-5p is an important inflammation-associated miRNA, whose abnormal expression has been associated with a variety of inflammation-related diseases. However, the role and signaling pathways targeted by miR-142-5p in acquired middle ear cholesteatoma (AMEC) have not been fully elucidated. Cyclin-dependent kinase 5 (CDK5), a special member of the CDK family compared with classic cyclins that plays a critical role in the inflammatory response. In this study, we investigated the roles of miR-142-5p and CDK5 in inflammatory responses in AMEC. Our results revealed that the expression of miR-142-5p was significantly reduced in AMEC, and was negatively correlated with the expression of CDK5 (r=-0.5451). We also found that miR-142-5p can inhibit CDK5 expression by directly target 3' untranslated region (UTR) of CDK5. Additionally, our findings indicated that the increased expression of CDK5 induces the secretion of inflammatory cytokines. In order to further confirm the involvement of miR-142-5p in the regulation of the inflammatory response in AMEC through its inhibitory effect on CDK5 expression, we studied the inflammatory response in HaCaT cells transfected with small interfering RNA against CDK5 (si-CDK5) and a miR-142-5p inhibitor. The results confirmed that miR-142-5p regulates the inflammatory response in AMEC by downregulating CDK5. In summary, miR-142-5p directly inhibits the CDK5-mediated upregulation of inflammatory cytokines in AMEC, which makes it a potential therapeutic target in this disease.
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Affiliation(s)
- Rongcui Sui
- Department of Otolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China; National Health Commission Key Laboratory of Otorhinolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China
| | - Wei Shi
- Department of Otolaryngology, Zhoucun District People's Hospital, 72 Mianhua Shi Road, Zibo, Shandong, China
| | - Shuhui Han
- Department of Otolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China; National Health Commission Key Laboratory of Otorhinolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China
| | - Xintai Fan
- Department of Otolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China; National Health Commission Key Laboratory of Otorhinolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China
| | - Xianzhao Zhang
- Department of Otolaryngology, The First People's Hospital of Jining, 6 Health Road, Jining, Shandong, China
| | - Na Wang
- Department of Otolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China; National Health Commission Key Laboratory of Otorhinolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China
| | - Hao Zhang
- Department of Otolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China; National Health Commission Key Laboratory of Otorhinolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China
| | - Anting Xu
- Department of Otolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China; National Health Commission Key Laboratory of Otorhinolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China.
| | - Chengcheng Liu
- Department of Otolaryngology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 274 Beiyuan Road, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Weiqi Road, Jinan, Shandong, China.
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19
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Hosseini K, Frenzel A, Fischer-Friedrich E. EMT changes actin cortex rheology in a cell-cycle-dependent manner. Biophys J 2021; 120:3516-3526. [PMID: 34022239 PMCID: PMC8391033 DOI: 10.1016/j.bpj.2021.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/29/2021] [Accepted: 05/13/2021] [Indexed: 01/06/2023] Open
Abstract
The actin cortex is a key structure for cellular mechanics and cellular migration. Accordingly, cancer cells were shown to change their actin cytoskeleton and their mechanical properties in correlation with different degrees of malignancy and metastatic potential. Epithelial-mesenchymal transition (EMT) is a cellular transformation associated with cancer progression and malignancy. To date, a detailed study of the effects of EMT on the frequency-dependent viscoelastic mechanics of the actin cortex is still lacking. In this work, we have used an established atomic force microscope-based method of cell confinement to quantify the rheology of the actin cortex of human breast, lung, and prostate epithelial cells before and after EMT in a frequency range of 0.02-2 Hz. Interestingly, we find for all cell lines opposite EMT-induced changes in interphase and mitosis; whereas the actin cortex softens upon EMT in interphase, the cortex stiffens in mitosis. Our rheological data can be accounted for by a rheological model with a characteristic timescale of slowest relaxation. In conclusion, our study discloses a consistent rheological trend induced by EMT in human cells of diverse tissue origin, reflecting major structural changes of the actin cytoskeleton upon EMT.
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Affiliation(s)
- Kamran Hosseini
- Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden, Germany; Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Annika Frenzel
- Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden, Germany; Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Elisabeth Fischer-Friedrich
- Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden, Germany; Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
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20
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Lu L, Yang L, Lu YP, Jiang Q, Wang CR, Liu CQ, Xu N, Jiang S, Zhang G, Lai EY, Han F, Lu YM. Endothelium-derived Cdk5 deficit aggravates air pollution-induced peripheral vasoconstriction through AT 1R upregulation. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 219:112314. [PMID: 33989920 DOI: 10.1016/j.ecoenv.2021.112314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 05/02/2021] [Accepted: 05/05/2021] [Indexed: 06/12/2023]
Abstract
PM2.5 infiltrates into circulation and increases the risk of systemic vascular dysfunction. As the first-line barrier against external stimuli, the molecular mechanism of the biological response of vascular endothelial cells to PM2.5 exposure remains unclear. In this study, 4-week-old mice were exposed to Hangzhou 'real' airborne PM2.5 for 2 months and were found to display bronchial and alveolar damage. Importantly, in the present study, we have demonstrated that Cdk5 deficit induced peripheral vasoconstriction through angiotensin II type 1 receptor under angiotensin II stimulation in Cdh5-cre;Cdk5f/n mice. In the brain, Cdk5 deficit increased the myogenic activity in the medullary arterioles under external pressure. On the other hand, no changes in cerebral blood flow and behavior patterns were observed in the Cdh5-cre;Cdk5f/n mice exposed to PM2.5. Therefore, our current findings indicate that CDK5 plays an important role in endothelium cell growth, migration, and molecular transduction, which is also a sensor for the response of vascular endothelial cells to PM2.5.
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Affiliation(s)
- Lu Lu
- Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Lin Yang
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; School of Medicine, Zhejiang University City College, Hangzhou 310058, Zhejiang, China
| | - Ya-Ping Lu
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Qin Jiang
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Cui-Rong Wang
- Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Cui-Qing Liu
- College of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Nan Xu
- Department of Physiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Shan Jiang
- Department of Physiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Gang Zhang
- Department of Neurology, Children's Hospital of Nanjing Medical University, Nanjing 211166, China
| | - En-Yin Lai
- Department of Physiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Feng Han
- Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
| | - Ying-Mei Lu
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
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Gilardi M, Bersini S, Valtorta S, Proietto M, Crippa M, Boussommier-Calleja A, Labelle M, Moresco RM, Vanoni M, Kamm RD, Moretti M. The driving role of the Cdk5/Tln1/FAK S732 axis in cancer cell extravasation dissected by human vascularized microfluidic models. Biomaterials 2021; 276:120975. [PMID: 34333365 DOI: 10.1016/j.biomaterials.2021.120975] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Understanding the molecular mechanisms of metastatic dissemination, the leading cause of death in cancer patients, is required to develop novel, effective therapies. Extravasation, an essential rate-limiting process in the metastatic cascade, includes three tightly coordinated steps: cancer cell adhesion to the endothelium, trans-endothelial migration, and early invasion into the secondary site. Focal adhesion proteins, including Tln1 and FAK, regulate the cytoskeleton dynamics: dysregulation of these proteins is often associated with metastatic progression and poor prognosis. METHODS Here, we studied the previously unexplored role of these targets in each extravasation step using engineered 3D in vitro models, which recapitulate the physiological vascular niche experienced by cancer cells during hematogenous metastasis. RESULTS Human breast cancer and fibrosarcoma cell lines respond to Cdk5/Tln1/FAK axis perturbation, impairing their metastatic potential. Vascular breaching requires actin polymerization-dependent invadopodia formation. Invadopodia generation requires the structural function of FAK and Tln1 rather than their activation through phosphorylation. Our data support that the inhibition of FAKS732 phosphorylation delocalizes ERK from the nucleus, decreasing ERK phosphorylated form. These findings indicate the critical role of these proteins in driving trans-endothelial migration. In fact, both knock-down experiments and chemical inhibition of FAK dramatically reduces lung colonization in vivo and TEM in microfluidic setting. Altogether, these data indicate that engineered 3D in vitro models coupled to in vivo models, genetic, biochemical, and imaging tools represent a powerful weapon to increase our understanding of metastatic progression. CONCLUSIONS These findings point to the need for further analyses of previously overlooked phosphorylation sites of FAK, such as the serine 732, and foster the development of new effective antimetastatic treatments targeting late events of the metastatic cascade.
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Affiliation(s)
- Mara Gilardi
- Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy; Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126, Milan, Italy; Institute of Pathology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland.
| | - Simone Bersini
- Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy; Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Lugano, Switzerland.
| | - Silvia Valtorta
- Università Degli Studi di Milano-Bicocca, Department of Medicine and Surgery and Tecnomed Foundation, Monza, Italy; Institute of Bioimaging and Molecular Physiology of National Researches Council (IBFM-CNR), Segrate, Italy.
| | - Marco Proietto
- Department of Biology-University of California - San Diego, La Jolla, CA, USA.
| | - Martina Crippa
- Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Lugano, Switzerland; Laboratory of Biological Structures Mechanics, Chemistry, Material and Chemical Engineering Department "Giulio Natta", Politecnico di Milano, Milan, Italy.
| | - Alexandra Boussommier-Calleja
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA.
| | - Myriam Labelle
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
| | - Rosa Maria Moresco
- Università Degli Studi di Milano-Bicocca, Department of Medicine and Surgery and Tecnomed Foundation, Monza, Italy; Institute of Bioimaging and Molecular Physiology of National Researches Council (IBFM-CNR), Segrate, Italy.
| | - Marco Vanoni
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126, Milan, Italy; ISBE.IT/ Centre of Systems Biology, Milano, Italy.
| | - Roger D Kamm
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA.
| | - Matteo Moretti
- Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy; Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Lugano, Switzerland; Euler Institute, Biomedical Sciences Faculty, Università Della Svizzera Italiana, Lugano, Switzerland.
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22
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Gao GB, Sun Y, Fang RD, Wang Y, Wang Y, He QY. Post-translational modifications of CDK5 and their biological roles in cancer. MOLECULAR BIOMEDICINE 2021; 2:22. [PMID: 35006426 PMCID: PMC8607427 DOI: 10.1186/s43556-021-00029-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 02/09/2021] [Indexed: 12/11/2022] Open
Abstract
Post-translational modifications (PTMs) of Cyclin-dependent kinase 5 (CDK5) have emerged as important regulatory mechanisms that modulate cancer development in patients. Though CDK5 is an atypical member of the cyclin-dependent kinase family, its aberrant expression links to cell proliferation, DNA damage response, apoptosis, migration and angiogenesis in cancer. Current studies suggested that, new PTMs on CDK5, including S-nitrosylation, sumoylation, and acetylation, serve as molecular switches to control the kinase activity of CDK5 in the cell. However, a majority of these modifications and their biological significance in cancer remain uncharacterized. In this review, we discussed the role of PTMs on CDK5-mediated signaling cascade, and their possible mechanisms of action in malignant tumors, as well as the challenges and future perspectives in this field. On the basis of the newly identified regulatory signaling pathways of CDK5 related to PTMs, researchers have investigated the cancer therapeutic potential of chemical compounds, small-molecule inhibitors, and competitive peptides by targeting CDK5 and its PTMs. Results of these preclinical studies demonstrated that targeting PTMs of CDK5 yields promising antitumor effects and that clinical translation of these therapeutic strategies is warranted.
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Affiliation(s)
- Gui-Bin Gao
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Yue Sun
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Run-Dong Fang
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Ying Wang
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Avenida da Universidade, Taipa, Macao SAR, China
| | - Yang Wang
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
| | - Qing-Yu He
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
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Li Z, Zhao Y. Influence of CDK5 Regulatory Subunit-Associated Protein 1-Like 1 Expression on the Survival of Patients with Non-Metastatic Nasopharyngeal Carcinoma. Cancer Manag Res 2021; 13:4821-4828. [PMID: 34168501 PMCID: PMC8216668 DOI: 10.2147/cmar.s314925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 05/26/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate the influence of CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1) expression on the survival of nasopharyngeal carcinoma (NPC) patients. METHODS A total of 140 non-metastatic NPC patients were retrospectively analyzed. The expression of CDKAL1 was detected by immunohistochemistry. RESULTS The CDKAL1-negative group exhibited better overall survival (OS) according to Kaplan-Meier curve analysis (p = 0.006), with 5-year OS rates for the CDKAL1-negative and -positive groups of 89.7% and 70.2%, respectively. The CDKAL1-negative group also exhibited a tendency toward a better progression-free survival (PFS) rate. Multivariate analysis showed that CDKAL1 expression was independently associated with both OS (p = 0.002) and PFS (p = 0.043). CONCLUSION CDKAL1 expression is an independent negative predictor of patient survival in non-metastatic NPC.
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Affiliation(s)
- Zhanzhan Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China
| | - Yajie Zhao
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China
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Sakai M, Yoshimura R. Mechanotransduction-Targeting Drugs Attenuate Stiffness-Induced Hepatic Stellate Cell Activation in Vitro. Biol Pharm Bull 2021; 44:416-421. [PMID: 33328427 DOI: 10.1248/bpb.b20-00815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In hepatitis, activated hepatic stellate cells (HSCs) produce collagens, causing liver fibrosis. Microenvironmental stiffness is a known trigger of HSC activation and is communicated through mechanotransduction. Cell proliferation, alpha smooth muscle actin (α-SMA) and collagen type Iα (Col1α) are indicative of activated HSCs. We hypothesized that certain compounds could interfere with the HSC's recognition of microenvironmental stiffness by blocking cell adhesion signaling. To verify the potential of mechanotransduction, and in particular of focal adhesion proteins, as liver fibrosis drug targets, we evaluated existing drugs. We examined the effects of the integrin antagonist, BS-1417; the focal adhesion kinase (FAK) inhibitor, defactinib; the cyclin-dependent kinase (CDK) inhibitor, roscovitine; and two microtubule modulators, paclitaxel and colchicine, on stiffness-induced HSC activation. To determine the extent of transforming growth factor β (TGF-β) participation in mechanotransduction, we measured gene expression levels of α-SMA and Col1α. We also measured ATP levels to determine cell number. Results revealed that interestingly, although TGF-β did not show additional HSC activation after stiffness stimulation, the TGF-β receptor inhibitor, SB525334, markedly suppressed stiffness-induced α-SMA and Col1α mRNA expression. BS-1417, roscovitine, defactinib and colchicine suppressed α-SMA and Col1α mRNA expression as well as the number of HSCs. Paclitaxel also suppressed stiffness-induced α-SMA mRNA expression and the number of HSCs, but mildly reduced that of Col1α mRNA. Together, these results show that an integrin antagonist and mechanotransduction-targeting drugs reduced stiffness-induced HSC activation in a dose-dependent fashion. The targeting of focal adhesion proteins involved in mechanotransduction is promising in liver fibrosis drug development.
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Affiliation(s)
- Mutsuko Sakai
- Department of Applied Biology, Kyoto Institute of Technology
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25
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Salem S, Mosaad R. Crosstalk between miR-203 and PKCθ regulates breast cancer stem cell markers. Ann Hum Genet 2021; 85:105-114. [PMID: 33576006 DOI: 10.1111/ahg.12415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 09/25/2020] [Accepted: 01/20/2021] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Protein kinase C theta (PKCθ) is expressed in ER-negative breast cancer and promotes cancer stem cells (CSCs) phenotype. PKCθ gene (PRKCQ) is predicted to be a target for tumor suppressor miR-203. Herein, we aim to validate this prediction and evaluate the ability of miR-203 to inhibit migration of breast cancer cell line enriched with CSCs, MDA-MB-231, via PRKCQ targeting. METHODS Cells were transfected with miR-203 mimic, PRKCQ siRNA and negative control; then real-time PCR, migration assay, western blotting, reporter assay, and chromatin accessibility assay were performed. RESULTS Our findings displayed significant decrease in PRKCQ mRNA level and luciferase signals in cells with restored miR-203 expression, therefore, validated PRKCQ as a direct target of miR-203. Additionally, inhibiting PRKCQ by siRNA led to significant inhibition of miR-203 expression and significant decrease of chromatin accessibility at miR-203 promoter region 466-291 upstream TSS. Both of miR-203 re-expression and PRKCQ suppression resulted in altering migration ability of MDA-MB-231 through regulating AKT pathway and genes involved in breast cancer stem cells, CD44 and ALDH1A3. Expression of CDK5, GIV, and NANOG was significantly downregulated in miR-203 mimic-transfected cells, while PRKCQ siRNA-transfected cells displayed downregulation of OCT3/4, SOX2, and NANOG. Furthermore, we found that miR-224 expression was enhanced while miR-150 was downregulated after ectopic expression of miR-203. CONCLUSION The study highlighted the negative feedback loop between miR-203 and its target PRKCQ and the interplay between them in regulating genes involved in BCSCs. The study also concluded "microRNA-mediated microRNA regulation" as an event in breast cancer cells.
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Affiliation(s)
- Sohair Salem
- Molecular Genetics and Enzymology Department, National Research Centre, Giza, Egypt
| | - Rehab Mosaad
- Molecular Genetics and Enzymology Department, National Research Centre, Giza, Egypt
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26
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Do PA, Lee CH. The Role of CDK5 in Tumours and Tumour Microenvironments. Cancers (Basel) 2020; 13:E101. [PMID: 33396266 PMCID: PMC7795262 DOI: 10.3390/cancers13010101] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/27/2020] [Accepted: 12/28/2020] [Indexed: 12/11/2022] Open
Abstract
Cyclin-dependent kinase 5 (CDK5), which belongs to the protein kinase family, regulates neuronal function but is also associated with cancer development and has been proposed as a target for cancer treatment. Indeed, CDK5 has roles in cell proliferation, apoptosis, angiogenesis, inflammation, and immune response. Aberrant CDK5 activation triggers tumour progression in numerous types of cancer. In this review, we summarise the role of CDK5 in cancer and neurons and CDK5 inhibitors. We expect that our review helps researchers to develop CDK5 inhibitors as treatments for refractory cancer.
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Affiliation(s)
| | - Chang Hoon Lee
- Phamaceutical Biochemistry, College of Pharmacy, BK21 FOUR Team, and Integrated Research Institute for Drug Development, Dongguk University, Goyang 100-715, Korea;
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27
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Papadopoulos A, Chalmantzi V, Mikhaylichenko O, Hyvönen M, Stellas D, Kanhere A, Heath J, Cunningham DL, Fotsis T, Murphy C. Combined transcriptomic and phosphoproteomic analysis of BMP4 signaling in human embryonic stem cells. Stem Cell Res 2020; 50:102133. [PMID: 33383406 DOI: 10.1016/j.scr.2020.102133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 11/08/2020] [Accepted: 12/14/2020] [Indexed: 12/17/2022] Open
Abstract
Human embryonic stem cells (hESCs) are an invaluable tool in the fields of embryology and regenerative medicine. Activin A and BMP4 are well-characterised growth factors implicated in pluripotency and differentiation. In the current study, hESCs are cultured in a modified version of mTeSR1, where low concentrations of ActivinA substitute for TGFβ. This culture system is further used to investigate the changes induced by BMP4 on hESCs by employing a combination of transcriptomic and phosphoproteomic approaches. Results indicate that in a pluripotent state, hESCs maintain WNT signaling under negative regulation by expressing pathway inhibitors. Initial stages of differentiation are characterized by upregulation of WNT pathway ligands, TGFβ pathway inhibitors which have been shown in Xenopus to expand the BMP signaling range essential for embryonic patterning, and mesendodermal transcripts. Moreover, BMP4 enhances the phosphorylation of proteins associated with migration and transcriptional regulation. Results further indicate the vital regulatory role of Activin A and BMP4 in crucial fate decisions in hESCs.
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Affiliation(s)
- Angelos Papadopoulos
- School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London SE5 9NU, United Kingdom
| | - Varvara Chalmantzi
- School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Olga Mikhaylichenko
- Cardiovascular Division, King's College London British Heart Foundation Centre of Excellence, London SE5 9NU, United Kingdom
| | - Marko Hyvönen
- Department of Biochemistry, University of Cambridge, United Kingdom
| | - Dimitris Stellas
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Aditi Kanhere
- School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom
| | - John Heath
- School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Debbie L Cunningham
- School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
| | - Theodore Fotsis
- Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, University Campus of Ioannina, 45110 Ioannina, Greece; Laboratory of Biology, Medical School, University of Ioannina, 45110 Ioannina, Greece
| | - Carol Murphy
- School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, University Campus of Ioannina, 45110 Ioannina, Greece.
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Qiao R, Di F, Wang J, Wei Y, Zhang Y, Xu T, Wang Y, Gu W, Han B, Yang R. The Association Between RAPSN Methylation in Peripheral Blood and Early Stage Lung Cancer Detected in Case-Control Cohort. Cancer Manag Res 2020; 12:11063-11075. [PMID: 33173339 PMCID: PMC7646459 DOI: 10.2147/cmar.s275321] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 10/03/2020] [Indexed: 12/24/2022] Open
Abstract
Background Early detection is essential to improve the survival and life quality of lung cancer (LC) patients. Changes of peripheral blood DNA methylation could be associated with malignancy but were mostly studied in Caucasians. Methods Here, in a Chinese population, we performed mass spectrometry assays to investigate the association between very early stage LC and methylation levels of RAPSN in the peripheral blood by a case–control cohort using of 221 LC patients (93.2% LC at stage I) and 285 unrelated cancer free control individuals. Results The odds ratios (ORs) of all CpG sites were evaluated for their risk to LC using inter-quartile analyses by logistic regression. In general, we observed an association between very early LC and decreased methylation of RAPSN_CpG_1.15 and RAPSN_CpG_3.4 (referring to Q4, OR range from 1.64 to 1.81, p<0.05). Stratified by gender, while hypomethylation of RAPSN_CpG_1.15, RAPSN_CpG_3.4 and RAPSN_CpG_7.14 were associated with LC in males (referring to Q4, ORs range from 1.94 to 2.31, p<0.05), RAPSN_CpG_2 and RAPSN_CpG_5 showed significantly lower methylation in female LC patients comparing to controls (referring to Q4, ORs range from 2.49 to 3.60, p<0.05). The risk of RAPSN hypomethylation to LC was enhanced by aging, and typically for people older than 55 years (referring to Q4, ORs range from 2.17 to 3.61 in six out of all 10 analyzed CpG groups, p<0.05). Conclusion Our study reveals an association between RAPSN hypomethylation in peripheral blood and LC and suggests the occurrence of altered blood-based methylation at the early stage of cancer.
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Affiliation(s)
- Rong Qiao
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, People's Republic of China
| | - Feifei Di
- Department of Research and Academic, Nanjing TANTICA Biotechnology Co. Ltd, Nanjing 210000, People's Republic of China
| | - Jun Wang
- Department of Research and Academic, Nanjing TANTICA Biotechnology Co. Ltd, Nanjing 210000, People's Republic of China
| | - Yujie Wei
- Department of Research and Academic, Nanjing TANTICA Biotechnology Co. Ltd, Nanjing 210000, People's Republic of China
| | - Yanman Zhang
- Department of Research and Academic, Nanjing TANTICA Biotechnology Co. Ltd, Nanjing 210000, People's Republic of China
| | - Tian Xu
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210000, People's Republic of China
| | - Yue Wang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, People's Republic of China
| | - Wanjian Gu
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210000, People's Republic of China
| | - Baohui Han
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, People's Republic of China
| | - Rongxi Yang
- Department of Research and Academic, Nanjing TANTICA Biotechnology Co. Ltd, Nanjing 210000, People's Republic of China.,Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210000, People's Republic of China
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Bei Y, Cheng N, Chen T, Shu Y, Yang Y, Yang N, Zhou X, Liu B, Wei J, Liu Q, Zheng W, Zhang W, Su H, Zhu W, Ji J, Shen P. CDK5 Inhibition Abrogates TNBC Stem-Cell Property and Enhances Anti-PD-1 Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2001417. [PMID: 33240752 PMCID: PMC7675186 DOI: 10.1002/advs.202001417] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 08/12/2020] [Indexed: 06/11/2023]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, in which the higher frequency of cancer stem cells (CSCs) correlates with the poor clinical outcome. An aberrant activation of CDK5 is found to associate with TNBC progression closely. CDK5 mediates PPARγ phosphorylation at its Ser 273, which induces CD44 isoform switching from CD44s to CD44v, resulting in an increase of stemness of TNBC cells. Blocking CDK5/pho-PPARγ significantly reduces CD44v+ BCSCs population in tumor tissues, thus abrogating metastatic progression in TNBC mouse model. Strikingly, diminishing stemness transformation reverses immunosuppressive microenvironment and enhances anti-PD-1 therapeutic efficacy on TNBC. Mechanistically, CDK5 switches the E3 ubiquitin ligase activity of PPARγ and directly protects ESRP1 from a ubiquitin-dependent proteolysis. This finding firstly indicates that CDK5 blockade can be a potent strategy to diminish stemness transformation and increase the response to PD-1 blockade in TNBC therapy.
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Affiliation(s)
- Yuncheng Bei
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
| | - Nan Cheng
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
| | - Ting Chen
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
- Laura and Isaac Perlmutter Cancer CenterNew York University Langone Medical CenterNew YorkNYUSA
| | - Yuxin Shu
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
| | - Ye Yang
- State Key Laboratory Cultivation Base for TCM Quality and EfficacyNanjing University of Chinese MedicineNanjing210023P. R. China
| | - Nanfei Yang
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
| | - Xinyu Zhou
- State Key Laboratory of Protein and Plant Gene ResearchCollege of Life SciencesPeking UniversityBeijing100871P. R. China
| | - Baorui Liu
- The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Jia Wei
- The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Qin Liu
- The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Wei Zheng
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
| | - Wenlong Zhang
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
| | - Huifang Su
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
| | - Wei‐Guo Zhu
- Guangdong Key Laboratory of Genome Instability and Human DiseaseShenzhen University Carson Cancer CenterDepartment of Biochemistry and Molecular BiologyShenzhen University School of MedicineShenzhen518060P. R. China
| | - Jianguo Ji
- State Key Laboratory of Protein and Plant Gene ResearchCollege of Life SciencesPeking UniversityBeijing100871P. R. China
| | - Pingping Shen
- State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer CenterNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210046P. R. China
- Guangdong Key Laboratory of Genome Instability and Human DiseaseShenzhen University Carson Cancer CenterDepartment of Biochemistry and Molecular BiologyShenzhen University School of MedicineShenzhen518060P. R. China
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Hosseini K, Taubenberger A, Werner C, Fischer‐Friedrich E. EMT-Induced Cell-Mechanical Changes Enhance Mitotic Rounding Strength. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2001276. [PMID: 33042748 PMCID: PMC7539203 DOI: 10.1002/advs.202001276] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/18/2020] [Indexed: 05/26/2023]
Abstract
To undergo mitosis successfully, most animal cells need to acquire a round shape to provide space for the mitotic spindle. This mitotic rounding relies on mechanical deformation of surrounding tissue and is driven by forces emanating from actomyosin contractility. Cancer cells are able to maintain successful mitosis in mechanically challenging environments such as the increasingly crowded environment of a growing tumor, thus, suggesting an enhanced ability of mitotic rounding in cancer. Here, it is shown that the epithelial-mesenchymal transition (EMT), a hallmark of cancer progression and metastasis, gives rise to cell-mechanical changes in breast epithelial cells. These changes are opposite in interphase and mitosis and correspond to an enhanced mitotic rounding strength. Furthermore, it is shown that cell-mechanical changes correlate with a strong EMT-induced change in the activity of Rho GTPases RhoA and Rac1. Accordingly, it is found that Rac1 inhibition rescues the EMT-induced cortex-mechanical phenotype. The findings hint at a new role of EMT in successful mitotic rounding and division in mechanically confined environments such as a growing tumor.
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Affiliation(s)
- Kamran Hosseini
- Biotechnology CenterTechnische Universität DresdenTatzberg 47–49Dresden01307Germany
- Cluster of Excellence Physics of LifeTechnische Universität DresdenDresden01062Germany
| | - Anna Taubenberger
- Biotechnology CenterTechnische Universität DresdenTatzberg 47–49Dresden01307Germany
| | - Carsten Werner
- Leibniz Institute of Polymer Research DresdenMax Bergmann CenterHohe Str. 6Dresden01069Germany
| | - Elisabeth Fischer‐Friedrich
- Biotechnology CenterTechnische Universität DresdenTatzberg 47–49Dresden01307Germany
- Cluster of Excellence Physics of LifeTechnische Universität DresdenDresden01062Germany
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Martin SG, Zhang S, Yang S, Saidy B, Deen S, Storr SJ. Dopamine and cAMP-regulated phosphoprotein 32kDa (DARPP-32), protein phosphatase-1 and cyclin-dependent kinase 5 expression in ovarian cancer. J Cell Mol Med 2020; 24:9165-9175. [PMID: 32588513 PMCID: PMC7417681 DOI: 10.1111/jcmm.15553] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 04/06/2020] [Accepted: 06/07/2020] [Indexed: 12/14/2022] Open
Abstract
Dopamine and cyclic‐AMP activated phosphoprotein Mr32kDa (DARPP‐32) is a central signalling protein in neurotransmission. Following DARPP‐32 phosphorylation by protein kinase A (PKA), DARPP‐32 becomes a potent protein phosphatase 1 (PP1) inhibitor. DARPP‐32 can itself inhibit PKA following DARPP‐32 phosphorylation by cyclin‐dependent kinase 5 (Cdk5). Increasing evidence indicates a role for DARPP‐32 and its associated signalling pathways in cancer; however, its role in ovarian cancer remains unclear. Using immunohistochemistry, expression of DARPP‐32, PP1 and Cdk5 was determined in a large cohort of primary tumours from ovarian cancer patients (n = 428, 445 and 434 respectively) to evaluate associations between clinical outcome and clinicopathological criteria. Low cytoplasmic and nuclear DARPP‐32 expression was associated with shorter patient overall survival and progression‐free survival (P = .001, .001, .004 and .037 respectively). Low nuclear and cytoplasmic DARPP‐32 expression remained significantly associated with overall survival in multivariate Cox regression (P = .045, hazard ratio (HR) = 0.734, 95% confidence interval (CI) = 0.542‐0.993 and P = .001, HR = 0.494, 95% CI = 0.325‐0.749, respectively). High cytoplasmic and nuclear PP1 expression was associated with shorter patient overall survival and high cytoplasmic PP1 expression with shorter progression‐free survival (P = .005, .033, and .037, respectively). High Cdk5 expression was associated with shorter progression‐free survival (P = .006). These data suggest a role for DARPP‐32 and associated signalling kinases as prognostic markers with clinical utility in ovarian cancer.
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Affiliation(s)
- Stewart G Martin
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Siwei Zhang
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Song Yang
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Behnaz Saidy
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | | | - Sarah J Storr
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
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Huang R, Chen Z, Li W, Fan C, Liu J. Immune system‑associated genes increase malignant progression and can be used to predict clinical outcome in patients with hepatocellular carcinoma. Int J Oncol 2020; 56:1199-1211. [PMID: 32319580 PMCID: PMC7115743 DOI: 10.3892/ijo.2020.4998] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/07/2020] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most malignant types of cancer, and is associated with high recurrence rates and a poor response to chemotherapy. Immune signatures in the microenvironment of HCC have not been well explored systematically. The aim of the present study was to identify prognostic immune signatures and build a nomogram for use in clinical evaluation. Using bioinformatics analysis, RNA‑seq data and overall survival (OS) information on 370 HCC cases from TCGA and 232 HCC cases from ICGC were analyzed. The differential expression of select immune genes, based on previously published studies, between HCC and adjacent tissue were analyzed using the limma package in R. Enrichment of pathways and gene ontology analysis was performed using clusterProfiler. Subsequently, univariate Cox regression analysis, Lasso penalty linear regression and multivariate Cox regression models were used to construct a model for immune risk score (IRS). The R packages, survival and survivalROC, were used to plot survival and the associated receiver operating characteristic curves. Infiltration of immune cells was calculated using Tumor IMmune Estimation Resource, with significance examined using a Pearson's correlation test. P<0.05 was considered significant. Based on the analysis, expression of 200 immune genes were upregulated and 47 immune genes were downregulated immune genes. In the multivariate Cox model, 5 genes (enhancer of zest homology 2, ferritin light chain, complement factor H related 3, isthmin 2, cyclin dependent kinase 5) were used to generate the IRS. By stratifying according to the median IRS, it was shown that patients with a high IRS had poor OS rates after 1, 2, 3 and 5 years, and this result was consistent across the testing, training and independent validation cohorts. Additionally, the IRS was correlated with the abundance of infiltrating immune cells. The nomogram built using IRS and clinical characteristics, was able to predict 1, 3 and 5 year OS with area under the curve values of >0.8. These results suggest that the model developed to calculate the IRS may be used to monitor the effectiveness of treatment strategies and for prognostic prediction.
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Affiliation(s)
- Rongfu Huang
- Department of Clinical Laboratory, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, Fujian 362000
| | - Zheng Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200000
| | | | - Chunmei Fan
- Department of Clinical Laboratory, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, Fujian 362000
| | - Jun Liu
- Department of Clinical Laboratory, Yue Bei People's Hospital, Shantou University Medical College, Shaoguan, Guangdong 512026, P.R. China
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Saidy B, Rakha EA, Green AR, Ellis IO, Martin SG, Storr SJ. Retrospective assessment of cyclin-dependent kinase 5 mRNA and protein expression and its association with patient survival in breast cancer. J Cell Mol Med 2020; 24:6263-6271. [PMID: 32352232 PMCID: PMC7294162 DOI: 10.1111/jcmm.15268] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/20/2020] [Accepted: 03/26/2020] [Indexed: 12/15/2022] Open
Abstract
Cyclin‐dependent kinase 5 (Cdk5) is an atypical member of the cyclin‐dependent kinase family and functions as a serine/threonine kinase that can be activated by non‐cyclin binding activators p35 or p39. Cdk5 expression and activity has been linked with the development and progression of cancer; however, its expression in breast cancer has not been fully described. Protein expression of Cdk5 was determined in a large cohort of early‐stage invasive breast cancer tumours (n = 1110) with long‐term follow‐up data using immunohistochemistry. Expression of CDK5 mRNA was assessed in the METABRIC cohort (n = 1980). Low nuclear and cytoplasmic expression of Cdk5 expression was significantly associated with shorter breast cancer‐specific survival (P = .004 and P = .001, respectively). Importantly, low nuclear and cytoplasmic expression of Cdk5 remained associated with survival in multivariate analysis, including potentially confounding factors (hazard ratio (HR) = 0.612, 95% confidence interval (CI) = 0.418‐0.896, P = .011 and HR = 0.507, 95% CI = 0.318‐0.809, P = .004, respectively). In addition, low nuclear and cytoplasmic expression of Cdk5 was significantly associated with clinicopathological criteria associated with adverse patient prognosis. Low CDK5 mRNA expression was associated with shorter patient survival (P = .005) in the METABRIC cohort; no associations between copy gain or loss and survival were observed. These data suggest that low Cdk5 expression is associated with poor clinical outcome of breast cancer patients and may be of clinical relevance.
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Affiliation(s)
- Behnaz Saidy
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Emad A Rakha
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Andrew R Green
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Ian O Ellis
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Stewart G Martin
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
| | - Sarah J Storr
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK
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Identification and Validation of an Individualized EMT-Related Prognostic Risk Score Formula in Gastric Adenocarcinoma Patients. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7082408. [PMID: 32309437 PMCID: PMC7142392 DOI: 10.1155/2020/7082408] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/30/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Background The epithelial-mesenchymal transition (EMT) is a pivotal process for fibrotic disease, embryonic development, and wound healing. Moreover, some evidence has proven that the disorder of EMT also plays an important role in carcinogenesis, especially invasion and metastasis of various tumors (Ritchie et al., 2015). Additionally, gastric adenocarcinoma (GAC) is a common gastrointestinal malignancy which is the fourth most commonly diagnosed tumor. Our study is aimed at identifying the prognostic value of EMT-related genes in gastric adenocarcinoma. Methods Firstly, high-throughput and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. 99 differentially expressed EMT-related genes (ERGs) were obtained in these gastric adenocarcinoma data. Secondly, GO and KEGG enrichment analyses show that EMT may promote gastric carcinogenesis. Next, 10 ERGs associated with prognosis of gastric adenocarcinoma patients are screened out by univariate Cox regression, and 6 pivotal prognostic ERGs (MMP8, MMP11, TFDP3, MYB, F2, and CNTN1) are identified through multivariate Cox regression. These 6 genes are confirmed with significant prognostic value in gastric adenocarcinoma through overall survival (OS) analysis. Finally, a risk score formula is constructed and tested in another gastric adenocarcinoma cohort from GEO. Results 99 differentially expressed EMT-related genes (ERGs) and their enriched pathways are identified. 10 ERGs are strongly related to the prognosis of GAC patients. A risk score formula of 6 prognosis-related ERGs used to predict the prognosis of gastric adenocarcinoma patients is identified and tested (risk score = 0.448115∗expression value of MMP8 + 0.378892∗expression value of MMP11 − 0.3226∗expression value of MYB + 1.322812∗expression value of TFDP3 + 0.325063∗expression value of F2 + 0.334197∗expression value of CNTN1). Conclusion This study provides a potential prognostic signature for predicting prognosis of gastric adenocarcinoma patients and molecular insights of EMT in gastric adenocarcinoma, and the formula focusing on the prognosis of gastric adenocarcinoma can be effective.
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Abstract
The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.
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Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, Yu M, Lin J, Cui Q. The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer. Int J Mol Sci 2020; 21:ijms21061960. [PMID: 32183020 PMCID: PMC7139603 DOI: 10.3390/ijms21061960] [Citation(s) in RCA: 351] [Impact Index Per Article: 70.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/23/2020] [Accepted: 02/24/2020] [Indexed: 12/12/2022] Open
Abstract
Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.
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Affiliation(s)
- Lei Ding
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Jiaqi Cao
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Wen Lin
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Hongjian Chen
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Xianhui Xiong
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Hongshun Ao
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Min Yu
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Jie Lin
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
| | - Qinghua Cui
- Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China; (L.D.); (J.C.); (W.L.); (H.C.); (X.X.); (H.A.); (M.Y.); (J.L.)
- Key Lab of Molecular Cancer Biology, Yunnan Education Department, Kunming 650091, China
- Correspondence:
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Liu J, Feng J, Li L, Lin L, Ji J, Lin C, Liu L, Zhang N, Duan D, Li Z, Huang B, Zhang Y, Lu J. Arginine methylation-dependent LSD1 stability promotes invasion and metastasis of breast cancer. EMBO Rep 2020; 21:e48597. [PMID: 31833203 PMCID: PMC7001506 DOI: 10.15252/embr.201948597] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 11/11/2019] [Accepted: 11/18/2019] [Indexed: 12/22/2022] Open
Abstract
Histone lysine demethylase 1 (LSD1), the first identified histone demethylase, is overexpressed in multiple tumor types, including breast cancer. However, the mechanisms that cause LSD1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 4 (PRMT4 or CARM1) dimethylates LSD1 at R838, which promotes the binding of the deubiquitinase USP7, resulting in the deubiquitination and stabilization of LSD1. Moreover, CARM1- and USP7-dependent LSD1 stabilization plays a key role in repressing E-cadherin and activating vimentin transcription through promoter H3K4me2 and H3K9me2 demethylation, respectively, which promotes invasion and metastasis of breast cancer cells. Consistently, LSD1 arginine methylation levels correlate with tumor grade in human malignant breast carcinoma samples. Our findings unveil a unique mechanism controlling LSD1 stability by arginine methylation, also highlighting the role of the CARM1-USP7-LSD1 axis in breast cancer progression.
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Affiliation(s)
- Jiwei Liu
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Jingxin Feng
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
- Present address:
Laboratory of Cellular OncologyCenter for Cancer Research (CCR)National Cancer Institute (NCI)BethesdaMDUSA
| | - Lili Li
- Key Laboratory of Cancer Prevention and TherapyDepartment of Bone and Soft Tissue OncologyNational Clinical Research Center for CancerTianjin Medical University Cancer Institute and HospitalTianjinChina
| | - Luyao Lin
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Jiafei Ji
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Cong Lin
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Lingxia Liu
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Na Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Dandan Duan
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Zhongwei Li
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Baiqu Huang
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Yu Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Jun Lu
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
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Sharma S, Sicinski P. A kinase of many talents: non-neuronal functions of CDK5 in development and disease. Open Biol 2020; 10:190287. [PMID: 31910742 PMCID: PMC7014686 DOI: 10.1098/rsob.190287] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The cyclin-dependent kinase 5 (CDK5) represents an unusual member of the family of cyclin-dependent kinases, which is activated upon binding to non-cyclin p35 and p39 proteins. The role of CDK5 in the nervous system has been very well established. In addition, there is growing evidence that CDK5 is also active in non-neuronal tissues, where it has been postulated to affect a variety of functions such as the immune response, angiogenesis, myogenesis, melanogenesis and regulation of insulin levels. Moreover, high levels of CDK5 have been observed in different tumour types, and CDK5 was proposed to play various roles in the tumorigenic process. In this review, we discuss these various CDK5 functions in normal physiology and disease, and highlight the therapeutic potential of targeting CDK5.
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Affiliation(s)
- Samanta Sharma
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.,Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.,Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
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Zhang J, Jiang H, Xu D, Wu WJ, Chen HD, He L. DNA-PKcs Mediates An Epithelial-Mesenchymal Transition Process Promoting Cutaneous Squamous Cell Carcinoma Invasion And Metastasis By Targeting The TGF-β1/Smad Signaling Pathway. Onco Targets Ther 2019; 12:9395-9405. [PMID: 31807020 PMCID: PMC6844265 DOI: 10.2147/ott.s205017] [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: 02/12/2019] [Accepted: 08/26/2019] [Indexed: 01/07/2023] Open
Abstract
Purpose DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has attracted extensive attention in various types of malignant tumors. However, the role of DNA-PKcs in cutaneous squamous cell carcinoma (cSCC) development has not been elucidated. In this study, we investigated the role of DNA-PKcs in cSCC and the molecular mechanisms of TGF-β1-induced cSCC progression mediated by DNA-PKcs. Methods We performed bioinformatic analysis and RT-PCR to examine the DNA-PKcs expression level in cSCC. Then, we downregulated DNA-PKcs using a DNA-PK-specific inhibitor or small interfering RNA (siRNA) to explore the effects of DNA-PKcs on SCL-1 cell migration and invasion. To further investigate the mechanism by which DNA-PKcs promotes cSCC progression, TGF-β1 and the TGF-β receptor (TGF-βR) I/II dual inhibitor LY2109761 were used to examine whether DNA-PKcs participates in TGF-β1/Smad signaling. Results DNA-PKcs expression was upregulated in cSCC. DNA-PK inhibition or expression knockdown resulted in inhibited migration and invasion and altered epithelial-mesenchymal transition (EMT) marker expression patterns in SCL-1 cells. Importantly, TGF-β1 mediated EMT induction in cSCC cells, and DNA-PKcs was identified as a TGF-β1-responsive gene. TGF-β1 promoted DNA-PKcs transcription, and DNA-PKcs enhanced the TGF-β1-induced EMT program involved in cSCC invasion and metastasis by phosphorylating Smad3. Conclusion This study is the first to show that DNA-PKcs mediates EMT to promote cSCC aggressiveness by targeting the TGF-β1/Smad signaling pathway, which provides insight into how DNA-PKcs impacts cSCC progression and identifies a new therapeutic target.
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Affiliation(s)
- Juan Zhang
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology & Venereology of Yunnan Province, Kunming, People's Republic of China
| | - Hui Jiang
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology & Venereology of Yunnan Province, Kunming, People's Republic of China
| | - Dan Xu
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology & Venereology of Yunnan Province, Kunming, People's Republic of China
| | - Wen-Juan Wu
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology & Venereology of Yunnan Province, Kunming, People's Republic of China
| | - Hong-Duo Chen
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Li He
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology & Venereology of Yunnan Province, Kunming, People's Republic of China
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Pecoraro A, Carotenuto P, Russo G, Russo A. Ribosomal protein uL3 targets E2F1 and Cyclin D1 in cancer cell response to nucleolar stress. Sci Rep 2019; 9:15431. [PMID: 31659203 PMCID: PMC6817900 DOI: 10.1038/s41598-019-51723-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/01/2019] [Indexed: 12/21/2022] Open
Abstract
Several experimental strategies in the treatment of cancer include drug alteration of cell cycle regulatory pathways as a useful strategy. Extra-ribosomal functions of human ribosomal protein L3 (uL3) may affect DNA repair, cell cycle arrest and apoptosis. In the present study, we demonstrated that uL3 is required for the activation of G1/S transition genes. Luciferase assays established that uL3 negatively regulates the activity of E2F1 promoter. Induced ribosome-free uL3 reduces Cyclin D1 mRNA and protein levels. Using protein/protein immunoprecipitation methods, we demonstrated that uL3 physically interacts with PARP-1 affecting E2F1 transcriptional activity. Our findings led to the identification of a new pathway mediated by uL3 involving E2F1 and Cyclin D1 in the regulation of cell cycle progression.
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Affiliation(s)
- Annalisa Pecoraro
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131, Naples, Italy
| | - Pietro Carotenuto
- The Institute of Cancer Research, Cancer Therapeutics Unit 15 Cotswold Road, Sutton, London, SM2 5NG, UK
| | - Giulia Russo
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131, Naples, Italy.
| | - Annapina Russo
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131, Naples, Italy.
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Cancer Stem Cells and Oral Carcinogenesis; a Review Article. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2019. [DOI: 10.5812/ijcm.96139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Ruiz de Porras V, Bystrup S, Cabrero-de Las Heras S, Musulén E, Palomero L, Alonso MH, Nieto R, Arango D, Moreno V, Queralt C, Manzano JL, Layos L, Bugés C, Martinez-Balibrea E. Tumor Expression of Cyclin-Dependent Kinase 5 (Cdk5) Is a Prognostic Biomarker and Predicts Outcome of Oxaliplatin-Treated Metastatic Colorectal Cancer Patients. Cancers (Basel) 2019; 11:cancers11101540. [PMID: 31614664 PMCID: PMC6826373 DOI: 10.3390/cancers11101540] [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: 09/05/2019] [Revised: 10/09/2019] [Accepted: 10/09/2019] [Indexed: 12/13/2022] Open
Abstract
In recent years, an increasing number of studies have shown that elevated expression of cyclin dependent kinase (Cdk5) contributes to the oncogenic initiation and progression of many types of cancers. In this study, we investigated the expression pattern of Cdk5 in colorectal cancer (CRC) cell lines and in a large number of tumor samples in order to evaluate its relevance in this pathogenesis and possible use as a prognostic marker. We found that Cdk5 is highly expressed and activated in CRC cell lines and that silencing of the kinase decreases their migration ability. In tumor tissues, Cdk5 is overexpressed compared to normal tissues due to a copy number gain. In patients with localized disease, we found that high Cdk5 levels correlate with poor prognosis, while in the metastatic setting, this was only the case for patients receiving an oxaliplatin-based treatment. When exploring the Cdk5 levels in the consensus molecular subtypes (CMS), we found the lowest levels in subtype 1, where high Cdk5 again was associated with a poorer prognosis. In conclusion, we confirm that Cdk5 is involved in CRC and disease progression and that it could serve as a prognostic and predictive biomarker in this disease.
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Affiliation(s)
- Vicenç Ruiz de Porras
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
| | - Sara Bystrup
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
| | - Sara Cabrero-de Las Heras
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
| | - Eva Musulén
- Department of Pathology, Hospital Universitari Germans Trias i Pujol, Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Department of Pathology, Hospital Universitari General de Catalunya, Grupo Quirónsalud, Pedro i Pons 1, 08195 Sant Cugat del Valles, Spain.
| | - Luis Palomero
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 08908 L'Hospitalet del Llobregat, Barcelona, Spain.
- ONCOBELL Program, Bellvitge Institute for Biomedical Research, 08908 L'Hospitalet del Llobregat, Barcelona, Spain.
| | - Maria Henar Alonso
- ONCOBELL Program, Bellvitge Institute for Biomedical Research, 08908 L'Hospitalet del Llobregat, Barcelona, Spain.
- Oncology Data Analytics Program, Institut Català d'Oncologia (ICO), 08908 Barcelona, Spain.
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08907 Barcelona, Spain.
| | - Rocio Nieto
- Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
| | - Diego Arango
- Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
| | - Víctor Moreno
- ONCOBELL Program, Bellvitge Institute for Biomedical Research, 08908 L'Hospitalet del Llobregat, Barcelona, Spain.
- Oncology Data Analytics Program, Institut Català d'Oncologia (ICO), 08908 Barcelona, Spain.
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08907 Barcelona, Spain.
| | - Cristina Queralt
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
| | - José Luis Manzano
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Medical Oncology Service, Catalan Institute of Oncology (ICO), 08908, Spain.
- B-ARGO group, Germans Trias I Pujol Research Institute (IGTP), Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
| | - Laura Layos
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Medical Oncology Service, Catalan Institute of Oncology (ICO), 08908, Spain.
- B-ARGO group, Germans Trias I Pujol Research Institute (IGTP), Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
| | - Cristina Bugés
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Medical Oncology Service, Catalan Institute of Oncology (ICO), 08908, Spain.
- B-ARGO group, Germans Trias I Pujol Research Institute (IGTP), Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
| | - Eva Martinez-Balibrea
- Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Ctra. Can Ruti- Camí de les escoles s/n, 08916 Badalona, Spain.
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Su CY, Yan RL, Hsu WH, Chu CT, Chang HC, Lai CC, Hsu HP, Chen HC. Phosphorylation of adducin-1 by cyclin-dependent kinase 5 is important for epidermal growth factor-induced cell migration. Sci Rep 2019; 9:13703. [PMID: 31548578 PMCID: PMC6757057 DOI: 10.1038/s41598-019-50275-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 08/31/2019] [Indexed: 12/14/2022] Open
Abstract
Cyclin-dependent kinase 5 (Cdk5) is predominantly expressed in neuron and plays an important role in neuronal physiology. Increasing evidence also indicates that Cdk5 may contribute to malignant progression of some types of cancers; however, the underlying mechanism remains elusive. In this study, we found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells. The capability of the phosphomimetic T724D mutant to bind to actin filaments was lower than that of wild type ADD1 and the T724A mutant. Cdk5 co-localized with ADD1 at the lamellipodia upon epidermal growth factor (EGF) stimulation. The increased lamellipodia formation and cell migration of human breast cancer cells MDA-MB-231 by EGF were accompanied by Cdk5 activation and increased phosphorylation of ADD1 at T724. Depletion of Cdk5 in MDA-MB-231 cells abrogated the effects of EGF on ADD1 T724 phosphorylation, lamellipodia formation, and cell migration. Likewise, depletion of ADD1 suppressed the effects of EGF on lamellipodia formation, cell migration, and invasion, all of which were restored by FLAG-ADD1 WT and the T724D mutant, but not the T724A mutant. Together, our results suggest that phosphorylation of ADD1 at T724 by Cdk5 is important for EGF-induced cell migration and invasion.
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Affiliation(s)
- Chia-Yi Su
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Ruei-Liang Yan
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Wen-Hsin Hsu
- Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Ching-Tung Chu
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
| | - Hsuan-Chia Chang
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Chen Lai
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hong-Chen Chen
- Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan. .,Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
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Roa Linares VC, Gallego Gómez JC. La pérdida de función de la quinasa dependiente de ciclina 5 (CDK5) altera el citoesqueleto y reduce la infección in vitro por el virus del dengue 2. ACTA BIOLÓGICA COLOMBIANA 2019. [DOI: 10.15446/abc.v24n3.79347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
La quinasa dependiente de ciclina 5 (CDK5) regula diversas funciones en neuronas, células endoteliales y epiteliales, entre ellas la dinámica del citoesqueleto. Así mismo, se ha reportado que componentes del citoesqueleto, tales como, filamentos de actina y microtúbulos juegan un rol importante durante la infección por el virus dengue (DENV). El objetivo del presente trabajo fue evaluar por dos métodos, inhibición química y silenciamiento génico, la participación de CDK5 durante la infección por DENV-2. La actividad antiviral de roscovitina fue evaluada usando ensayos de Unidades Formadoras de Placa (PFU). La eficiencia de transfección y el silenciamiento de CDK5, empleando miARNs artificiales, se determinó por citometría de flujo. El efecto sobre la proteína de envoltura viral y elementos del citoesqueleto se evidenció mediante microscopia avanzada de fluorescencia y análisis de imágenes. Roscovitina mostró actividad antiviral en etapas pre y post-infectivas en una forma dependiente de la dosis. El tratamiento con roscovitina y miRCDK5 mostró ser efectivo reduciendo la cantidad de CDK5 en células no infectadas. En células infectadas y transfectadas con miRCDK5, así como tratadas con el inhibidor, se observó una reducción significativa de la proteína de envoltura viral; sin embargo, no se encontró reducción significativa de CDK5. Además, el tratamiento con roscovitina indujo cambios celulares morfológicos evidentes en células infectadas. Los resultados indican la potencial participación de CDK5 durante la infección por DENV-2, posiblemente mediando la traducción proteica o la replicación del genoma viral a través de la regulación de la dinámica del citoesqueleto. Se requieren datos adicionales para esclarecer la mecanística del fenómeno usando métodos alternativos.
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Uretmen Kagiali ZC, Sanal E, Karayel Ö, Polat AN, Saatci Ö, Ersan PG, Trappe K, Renard BY, Önder TT, Tuncbag N, Şahin Ö, Ozlu N. Systems-level Analysis Reveals Multiple Modulators of Epithelial-mesenchymal Transition and Identifies DNAJB4 and CD81 as Novel Metastasis Inducers in Breast Cancer. Mol Cell Proteomics 2019; 18:1756-1771. [PMID: 31221721 PMCID: PMC6731077 DOI: 10.1074/mcp.ra119.001446] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/21/2019] [Indexed: 01/01/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is driven by complex signaling events that induce dramatic biochemical and morphological changes whereby epithelial cells are converted into cancer cells. However, the underlying molecular mechanisms remain elusive. Here, we used mass spectrometry based quantitative proteomics approach to systematically analyze the post-translational biochemical changes that drive differentiation of human mammary epithelial (HMLE) cells into mesenchymal. We identified 314 proteins out of more than 6,000 unique proteins and 871 phosphopeptides out of more than 7,000 unique phosphopeptides as differentially regulated. We found that phosphoproteome is more unstable and prone to changes during EMT compared with the proteome and multiple alterations at proteome level are not thoroughly represented by transcriptional data highlighting the necessity of proteome level analysis. We discovered cell state specific signaling pathways, such as Hippo, sphingolipid signaling, and unfolded protein response (UPR) by modeling the networks of regulated proteins and potential kinase-substrate groups. We identified two novel factors for EMT whose expression increased on EMT induction: DnaJ heat shock protein family (Hsp40) member B4 (DNAJB4) and cluster of differentiation 81 (CD81). Suppression of DNAJB4 or CD81 in mesenchymal breast cancer cells resulted in decreased cell migration in vitro and led to reduced primary tumor growth, extravasation, and lung metastasis in vivo Overall, we performed the global proteomic and phosphoproteomic analyses of EMT, identified and validated new mRNA and/or protein level modulators of EMT. This work also provides a unique platform and resource for future studies focusing on metastasis and drug resistance.
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Affiliation(s)
| | - Erdem Sanal
- ‡Department of Molecular Biology and Genetics, Koç University, 34450 Istanbul, Turkey
| | - Özge Karayel
- ‡Department of Molecular Biology and Genetics, Koç University, 34450 Istanbul, Turkey
| | - Ayse Nur Polat
- ‡Department of Molecular Biology and Genetics, Koç University, 34450 Istanbul, Turkey
| | - Özge Saatci
- §Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208
| | - Pelin Gülizar Ersan
- ¶Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Kathrin Trappe
- ‖Bioinformatics Unit (MF1), Robert Koch Institute, 13353 Berlin, Germany
| | - Bernhard Y Renard
- ‖Bioinformatics Unit (MF1), Robert Koch Institute, 13353 Berlin, Germany
| | - Tamer T Önder
- **Koç University Research Center for Translational Medicine (KUTTAM), 34450 Istanbul, Turkey; ‡‡School of Medicine, Koç University, 34450 Istanbul, Turkey
| | - Nurcan Tuncbag
- §§Graduate School of Informatics, Department of Health Informatics, METU, 06800 Ankara, Turkey; ¶¶Cancer Systems Biology Laboratory (CanSyL), METU, 06800 Ankara, Turkey
| | - Özgür Şahin
- §Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208; ¶Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, 06800 Ankara, Turkey
| | - Nurhan Ozlu
- ‡Department of Molecular Biology and Genetics, Koç University, 34450 Istanbul, Turkey; **Koç University Research Center for Translational Medicine (KUTTAM), 34450 Istanbul, Turkey.
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Zhang J, Zhao D, Li Q, Du X, Liu Y, Dai X, Hong L. Upregulation of LSD1 promotes migration and invasion in gastric cancer through facilitating EMT. Cancer Manag Res 2019; 11:4481-4491. [PMID: 31191010 PMCID: PMC6526921 DOI: 10.2147/cmar.s186649] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background Gastric cancer (GC) is a common malignant tumor of the digestive system. In addition, GC metastasis is an extremely complicated process. A previous study has found that lysine-specific demethylase 1 (LSD1) is abnormal expression in a variety of cancers and its overexpression correlates with aggressive disease and poor outcome. Methods qRT-PCR and Western blot assays were used to assess the expression of LSD1 in GC tissue samples and cell lines. Colony formation assay, CCK-8 assay, scratch-wound assay and transwell invasion, were performed to determine the effect of LSD1 on cell proliferation and migration as well as invasion in GC. Results Our results show that LSD1 was up-regulated in GC tumor tissues and cell lines, and high expression level of LSD1 was found to be positively correlated with tumor size, lymph node metastasis and pathological grade. Moreover, LSD1 promoted cell proliferation, migration and invasion of GC. In addition, LSD1 regulated E-cadherin expression through demethylating H3K4me2, thereby promoting EMT in GC. Conclusion Our work indicated that LSD1 may be used as a potential target of gastric cancer.
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Affiliation(s)
- Jin Zhang
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, P.R. China,
| | - Donghui Zhao
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, P.R. China,
| | - Qingjun Li
- Department of Neurology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, P.R. China
| | - Xiuluan Du
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, P.R. China,
| | - Yanxiang Liu
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, P.R. China,
| | - Xin Dai
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, P.R. China,
| | - Lianqing Hong
- Department of Pathology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital Affiliated with Nanjing University of Chinese Medicine, Nanjing, P.R. China,
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Chi TF, Horbach T, Götz C, Kietzmann T, Dimova EY. Cyclin-Dependent Kinase 5 (CDK5)-Mediated Phosphorylation of Upstream Stimulatory Factor 2 (USF2) Contributes to Carcinogenesis. Cancers (Basel) 2019; 11:cancers11040523. [PMID: 31013770 PMCID: PMC6521020 DOI: 10.3390/cancers11040523] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 03/30/2019] [Accepted: 04/08/2019] [Indexed: 12/12/2022] Open
Abstract
The transcription factor USF2 is supposed to have an important role in tumor development. However, the regulatory mechanisms contributing to the function of USF2 are largely unknown. Cyclin-dependent kinase 5 (CDK5) seems to be of importance since high levels of CDK5 were found in different cancers associated with high USF2 expression. Here, we identified USF2 as a phosphorylation target of CDK5. USF2 is phosphorylated by CDK5 at two serine residues, serine 155 and serine 222. Further, phosphorylation of USF2 at these residues was shown to stabilize the protein and to regulate cellular growth and migration. Altogether, these results delineate the importance of the CDK5-USF2 interplay in cancer cells.
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Affiliation(s)
- Tabughang Franklin Chi
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland; (T.F.C.); (T.K.)
| | - Tina Horbach
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland; (T.F.C.); (T.K.)
| | - Claudia Götz
- Medical Biochemistry and Molecular Biology, Saarland University, 66421 Homburg, Germany;
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland; (T.F.C.); (T.K.)
| | - Elitsa Y. Dimova
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland; (T.F.C.); (T.K.)
- Correspondence: ; Tel.: +358-0-294-485-785; Fax: +358-8-553-114
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Cortés N, Guzmán-Martínez L, Andrade V, González A, Maccioni RB. CDK5: A Unique CDK and Its Multiple Roles in the Nervous System. J Alzheimers Dis 2019; 68:843-855. [DOI: 10.3233/jad-180792] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Nicole Cortés
- Laboratory of Neurosciences, Faculty of Sciences, University of Chile, Santiago, Chile
- International Center for Biomedicine (ICC), Santiago, Chile
| | - Leonardo Guzmán-Martínez
- Laboratory of Neurosciences, Faculty of Sciences, University of Chile, Santiago, Chile
- International Center for Biomedicine (ICC), Santiago, Chile
| | - Víctor Andrade
- Laboratory of Neurosciences, Faculty of Sciences, University of Chile, Santiago, Chile
- International Center for Biomedicine (ICC), Santiago, Chile
| | - Andrea González
- Laboratory of Neurosciences, Faculty of Sciences, University of Chile, Santiago, Chile
- International Center for Biomedicine (ICC), Santiago, Chile
| | - Ricardo B. Maccioni
- Laboratory of Neurosciences, Faculty of Sciences, University of Chile, Santiago, Chile
- International Center for Biomedicine (ICC), Santiago, Chile
- Department of Neurological Sciences, Faculty of Medicine, East Campus, University of Chile, Santiago, Chile
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Lu J, Lin JX, Zhang PY, Sun YQ, Li P, Xie JW, Wang JB, Chen QY, Cao LL, Lin Y, Huang CM, Zheng CH. CDK5 suppresses the metastasis of gastric cancer cells by interacting with and regulating PP2A. Oncol Rep 2019; 41:779-788. [PMID: 30431123 PMCID: PMC6312987 DOI: 10.3892/or.2018.6860] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 10/16/2018] [Indexed: 02/07/2023] Open
Abstract
Several previous studies have demonstrated that cyclin‑dependent kinase (CDK)‑5 expression serves an important role in promoting the development of malignant tumours. We have previously reported that CDK5 suppresses gastric tumourigenesis. The aim of the present study was to investigate the mechanistic basis of CDK5. The results of immunoprecipitation and western blot analysis demonstrated that CDK5 could interact with serine/threonine‑protein phosphatase 2A (PP2A). The use of an inhibitor of PP2A in CDK5‑overexpressing gastric cancer (GC) cell lines antagonized CDK5‑mediated suppression in GC cells. Further analysis revealed that PP2A expression was downregulated in GC and patients with low levels of PP2A had worse survival outcomes than those with high levels of PP2A (P=0.035). Therefore, the present study provided a novel mechanism for CDK5‑mediated tumour suppression, suggesting that CDK5 may be an attractive target for future therapeutic strategies for treating GC. In addition, low levels of PP2A may indicate a tendency for poor prognosis in patients with GC.
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Affiliation(s)
- Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Peng-Yang Zhang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Yu-Qin Sun
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
| | - Yao Lin
- College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350000, P.R. China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350000, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350000, P.R. China
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Le Rhun E, Achenbach C, Lohmann B, Silginer M, Schneider H, Meetze K, Szabo E, Weller M. Profound, durable and MGMT‐independent sensitivity of glioblastoma cells to cyclin‐dependent kinase inhibition. Int J Cancer 2019; 145:242-253. [DOI: 10.1002/ijc.32069] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 12/06/2018] [Indexed: 12/28/2022]
Affiliation(s)
- Emilie Le Rhun
- Laboratory of Molecular Neuro‐Oncology, Department of NeurologyUniversity Hospital and University of Zurich Zurich Switzerland
| | - Caroline Achenbach
- Laboratory of Molecular Neuro‐Oncology, Department of NeurologyUniversity Hospital and University of Zurich Zurich Switzerland
| | - Birthe Lohmann
- Laboratory of Molecular Neuro‐Oncology, Department of NeurologyUniversity Hospital and University of Zurich Zurich Switzerland
| | - Manuela Silginer
- Laboratory of Molecular Neuro‐Oncology, Department of NeurologyUniversity Hospital and University of Zurich Zurich Switzerland
| | - Hannah Schneider
- Laboratory of Molecular Neuro‐Oncology, Department of NeurologyUniversity Hospital and University of Zurich Zurich Switzerland
| | | | - Emese Szabo
- Laboratory of Molecular Neuro‐Oncology, Department of NeurologyUniversity Hospital and University of Zurich Zurich Switzerland
| | - Michael Weller
- Laboratory of Molecular Neuro‐Oncology, Department of NeurologyUniversity Hospital and University of Zurich Zurich Switzerland
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