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Passi M, Stöckl JB, Fröhlich T, Moser S, Vollmar AM, Zahler S. CDK5 interacts with MST2 and modulates the Hippo signalling pathway. FEBS Open Bio 2025; 15:647-660. [PMID: 39739588 PMCID: PMC11961382 DOI: 10.1002/2211-5463.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 12/16/2024] [Indexed: 01/02/2025] Open
Abstract
MST2 (STK3) is a major upstream kinase in the Hippo signalling pathway, an evolutionary conserved pathway in regulation of organ size, self-renewal and tissue homeostasis. Its downstream effectors are the transcriptional regulators YAP and TAZ. This pathway is regulated by a variety of factors, such as substrate stiffness or cell-cell contacts. Using a yeast two-hybrid screen, we detected a novel interaction between the kinases MST2 and CDK5, which we further confirmed by co-immunoprecipitation experiments. Cyclin-dependent kinase 5 (CDK5) is an unusual member of the family of cyclin-dependent kinases, involved in tumour growth and angiogenesis. Although a link between CDK5 and Hippo has been previously postulated, the mode of action is still elusive. Here, we show that knockdown of CDK5 causes reduced transcriptional activity of YAP and that CDK5 influences the phosphorylation levels of the Hippo upstream kinase LATS1. Moreover, a phosphoproteomics approach revealed that CDK5 interferes with the phosphorylation of DLG5, another upstream kinase, which regulates the Hippo pathway. Hence, CDK5 seems to act as a signalling hub for integrating the Hippo pathway and other signalling cascades. These interactions might have important implications for the use of CDK5 inhibitors, which are already in clinical use for tumour diseases.
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Affiliation(s)
- Mehak Passi
- Center for Drug ResearchLudwig‐Maximilians‐University MunichGermany
| | - Jan B. Stöckl
- Laboratory for Functional Genome Analysis, Gene Center MunichLudwig‐Maximilians‐University MunichGermany
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis, Gene Center MunichLudwig‐Maximilians‐University MunichGermany
| | - Simone Moser
- Center for Drug ResearchLudwig‐Maximilians‐University MunichGermany
- Institute of PharmacyUniversity of InnsbruckAustria
| | | | - Stefan Zahler
- Center for Drug ResearchLudwig‐Maximilians‐University MunichGermany
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2
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Tan X, Xun L, Yin Q, Chen C, Zhang T, Shen T. Epigenetic Modifications in HBV-Related Hepatocellular Carcinoma. J Viral Hepat 2025; 32:e14044. [PMID: 39868653 DOI: 10.1111/jvh.14044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/13/2024] [Accepted: 11/30/2024] [Indexed: 01/28/2025]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Hepatitis B virus (HBV) is the main pathogen for HCC development. HBV covalently closed circular DNA (cccDNA) forms extra-host chromatin-like minichromosomes in the nucleus of hepatocytes with host histones, non-histones, HBV X protein (HBx) and HBV core protein (HBc). Epigenetic alterations are dynamic and reversible, which regulate gene expression without altering the DNA sequence and play a pivotal role in the regulation of HCC onset and progression. The aim of this review is to elucidate the deregulation of epigenetic mechanisms involved in the pathogenesis of HBV-related HCC (HBV-HCC), including post-translational histone and non-histone modifications, DNA hypermethylation and hypomethylation, non-coding RNA modification on HBV cccDNA minichromosomes and host factors, effecting the replication/transcription of HBV cccDNA and transcription/translation of host genes, and thus HBV-HCC progression. It is expected that the epigenetic regulation perspective provides new ways for more in-depth development of therapeutic control of HBV-HCC.
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Affiliation(s)
- Xiaoqing Tan
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
| | - Linting Xun
- Department of Gastroenterology, the First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People's Republic of China
| | - Qi Yin
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, People's Republic of China, China
| | - Chaohui Chen
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Tao Zhang
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
| | - Tao Shen
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
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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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4
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Cao D, Wang YN, Sun CY, Li H, Ren G, Zhou YF, Zhang MY, Wang SC, Mai SJ, Wang HY. MAF1 inhibits hepatocarcinogenesis by fostering an immunostimulatory tumor microenvironment. J Immunother Cancer 2025; 13:e009656. [PMID: 39800372 PMCID: PMC11749189 DOI: 10.1136/jitc-2024-009656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 12/06/2024] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND The biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in HCC is crucial for developing novel immunotherapy strategies and enhancing clinical responses to treatment for patients with HCC. METHODS Mice were subjected to hydrodynamic tail vein injections of transposon vectors to overexpress AKT/NRas, or c-Myc, with or without wild-type (WT) or mutant-activated (-4A) MAF1, or short-hairpin MAF1 (shMAF1). Liver tissues and tumors were harvested and analyzed using histology, immunohistochemistry, immunoblotting, quantitative reverse-transcription PCR, and flow cytometry. MAF1 was overexpressed or knocked down in HCC cells via lentiviral transfection. Cell lines were analyzed using RNA sequencing, immunoblotting, dual luciferase reporter, and chromatin precipitation assays. RESULTS Both MAF1-WT and MAF1-4A proteins significantly inhibit hepatocarcinogenesis in mice, with the mutant form exhibiting a stronger suppressive effect. Although MAF1 knockdown alone does not induce abnormalities in the mouse liver, it accelerates c-Myc-induced carcinogenesis. Our results provide the first in vivo evidence that MAF1 plays a tumor suppressor role by activating PTEN to suppress the AKT-mammalian target of rapamycin signaling pathway during hepatocarcinogenesis in physiologically relevant tumor models. More importantly, we found that MAF1 not only enhances the intratumoral infiltration of CD8+ T cells by increasing CXCL10 secretion but also enhances their functional activity by inhibiting PDL1 transcription in mouse liver cancer, which were confirmed in human HCC or in vitro experiments. Furthermore, PDL1 overexpression accelerates mouse hepatocarcinogenesis by antagonizing the tumor-suppressive role of MAF1. CONCLUSIONS Our study uncovers a novel anti-tumor immunity of MAF1 in hepatocarcinogenesis and human HCC. These findings suggest that the stimulated MAF1 could potentially improve immunotherapy in combination with immune checkpoint inhibitors in HCC patients, especially in those with an absence of T cells in HCC tissues.
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Affiliation(s)
- Di Cao
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yue-Ning Wang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chao-Yue Sun
- College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, China
| | - Haojiang Li
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ge Ren
- Department of Health Technology and Informatics, Hong Kong Polytechnic University University Learning Hub, Kowloon, Hong Kong
| | - Yu-Feng Zhou
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuo-Cheng Wang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shi-Juan Mai
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Song M, Qiang Y, Zhao X, Song F. Cyclin-dependent Kinase 5 and Neurodegenerative Diseases. Mol Neurobiol 2024; 61:7287-7302. [PMID: 38378992 DOI: 10.1007/s12035-024-04047-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 02/07/2024] [Indexed: 02/22/2024]
Abstract
Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.
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Affiliation(s)
- Mingxue Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong, 250012, People's Republic of China
| | - Yalong Qiang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong, 250012, People's Republic of China
| | - Xiulan Zhao
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong, 250012, People's Republic of China
| | - Fuyong Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong, 250012, People's Republic of China.
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6
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Rossini E, Tamburello M, Abate A, Zini S, Ribaudo G, Gianoncelli A, Calza S, Valcamonico F, Suardi NR, Mirabella G, Berruti A, Sigala S. The CDK Inhibitor Dinaciclib Improves Cisplatin Response in Nonseminomatous Testicular Cancer: A Preclinical Study. Cells 2024; 13:368. [PMID: 38474332 PMCID: PMC10931172 DOI: 10.3390/cells13050368] [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: 12/13/2023] [Revised: 02/08/2024] [Accepted: 02/17/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). METHODS The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. RESULTS Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. CONCLUSIONS Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.
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Affiliation(s)
- Elisa Rossini
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (E.R.); (A.A.); (S.Z.); (G.R.); (A.G.); (S.S.)
| | - Mariangela Tamburello
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (E.R.); (A.A.); (S.Z.); (G.R.); (A.G.); (S.S.)
| | - Andrea Abate
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (E.R.); (A.A.); (S.Z.); (G.R.); (A.G.); (S.S.)
| | - Silvia Zini
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (E.R.); (A.A.); (S.Z.); (G.R.); (A.G.); (S.S.)
| | - Giovanni Ribaudo
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (E.R.); (A.A.); (S.Z.); (G.R.); (A.G.); (S.S.)
| | - Alessandra Gianoncelli
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (E.R.); (A.A.); (S.Z.); (G.R.); (A.G.); (S.S.)
| | - Stefano Calza
- Unit of Biostatistics and Bioinformatics, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy;
| | - Francesca Valcamonico
- Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at ASST Spedali Civili di Brescia, 25123 Brescia, Italy; (F.V.); (A.B.)
| | - Nazareno R. Suardi
- Urology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at ASST Spedali Civili di Brescia, 25123 Brescia, Italy; (N.R.S.); (G.M.)
| | - Giuseppe Mirabella
- Urology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at ASST Spedali Civili di Brescia, 25123 Brescia, Italy; (N.R.S.); (G.M.)
| | - Alfredo Berruti
- Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at ASST Spedali Civili di Brescia, 25123 Brescia, Italy; (F.V.); (A.B.)
| | - Sandra Sigala
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (E.R.); (A.A.); (S.Z.); (G.R.); (A.G.); (S.S.)
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Jiang Y, Xu Y, Zhu C, Xu G, Xu L, Rao Z, Zhou L, Jiang P, Malik S, Fang J, Lin H, Zhang M. STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice. Sci Signal 2023; 16:eadd2282. [PMID: 38051779 PMCID: PMC10907978 DOI: 10.1126/scisignal.add2282] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 11/14/2023] [Indexed: 12/07/2023]
Abstract
Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A, which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7, which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.
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Affiliation(s)
- Yi Jiang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Yuejie Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210008, China
- Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Chengliang Zhu
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Center for Drug Safety Evaluation and Research of Zhejiang University, Zhejiang University, Hangzhou 310058, China
| | - Guifang Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210008, China
| | - Lei Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210008, China
| | - Zijian Rao
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lixing Zhou
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ping Jiang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing 210008, China
| | - Sara Malik
- Northwestern University Feinberg School of Medicine, Chicago, 60611, IL, United States
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Hening Lin
- Howard Hughes Medical Institute; Department of Chemistry and Chemical Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, United States
| | - Mingming Zhang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
- Howard Hughes Medical Institute; Department of Chemistry and Chemical Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, United States
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Zhang R, Wang J, Du Y, Yu Z, Wang Y, Jiang Y, Wu Y, Le T, Li Z, Zhang G, Lv L, Ma H. CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma. J Immunother Cancer 2023; 11:e007529. [PMID: 38007240 PMCID: PMC10679996 DOI: 10.1136/jitc-2023-007529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2023] [Indexed: 11/27/2023] Open
Abstract
BACKGROUND In the past few years, immunotherapies of hepatocellular carcinoma (HCC) targeting programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1), have achieved durable clinical benefits. However, only a fraction of HCC patients showed objective clinical response to PD-1/PD-L1 blockade alone. Despite the impact on post-translational modifications of PD-L1 being substantial, its significance in resistance to HCC immunotherapy remains poorly defined. METHODS Cyclin-dependent kinase 5 (CDK5) expression was knocked down in HCC cells, CDK5 and PD-L1 protein levels were examined by Western blot. Coimmunoprecipitation was conducted to evaluate the interaction between proteins. Preclinical HCC mice model was constructed to evaluate the effect of CDK5 inhibitor alone or in combination with PD-1 antibody. Clinical HCC samples were used to elucidate the clinical relevance of CDK5, PD-L1, and PD-L1 T290 phosphorylation in HCC. RESULTS We find that CDK5 deficiency upregulates PD-L1 protein expression in HCC cells and decipher a novel molecular mechanism under which PD-L1 is downregulated by CDK5, that is, CDK5 mediated PD-L1 phosphorylation at T290 promotes its binding with chaperon protein heat-shock cognate protein 70 (HSC70) and degradation through chaperon-mediated autophagy. Notably, treatment of CDK5 inhibitor, PNU112455A, effectively upregulates the tumorous PD-L1 level, promotes the response to anti-PD-1 immunotherapy,and prolongs the survival time of mice bearing HCC tumors. What is more, the T290 phosphorylation status of PD-L1 correlates with the prognosis of HCC. CONCLUSIONS Targeting CDK5 can synergize with PD-1 blockade to suppress HCC growth, which may have clinical benefits. Our study reveals a unique regulation of the degradation of PD-L1 in HCC, and provides an attractive therapeutic target, a potential drug, and a new prognostic marker for the clinical treatment of HCC.
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Affiliation(s)
- Ruonan Zhang
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jie Wang
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Yu Du
- Nourse Centre for Pet Nutrition, Wuhu, Anhui, China
| | - Ze Yu
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Yihan Wang
- School of Management, Xi'an Jiaotong University, Xi'an, Shanxi, China
| | - Yixiao Jiang
- Department of General Surgery, Zhoushan Hospital, Zhoushan, Zhejiang, China
| | - Yixin Wu
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Ting Le
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Ziqi Li
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Guoqiang Zhang
- Department of General Surgery, Zhoushan Hospital, Zhoushan, Zhejiang, China
| | - Lei Lv
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Haijie Ma
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China
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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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10
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Kawano M, Tanaka K, Itonaga I, Iwasaki T, Kubota Y, Tsumura H. Tumor-suppressive microRNA-152 inhibits the proliferation of Ewing's sarcoma cells by targeting CDK5R1. Sci Rep 2023; 13:18546. [PMID: 37899376 PMCID: PMC10613623 DOI: 10.1038/s41598-023-45833-6] [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: 03/26/2023] [Accepted: 10/24/2023] [Indexed: 10/31/2023] Open
Abstract
We elucidated the mechanism through which the reduced expression of miR-152 leads to the overexpression of its target cyclin-dependent kinase-5 activator 1 (CDK5R1) in Ewing's sarcoma (ES) cells and the role of this mechanism in the proliferation of ES cells. To explore possible oncogenic factors in ES, we conducted microarray-based investigation and profiled the changes in miRNA expression and their effects on downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). miR-152 was significantly downregulated, while cyclin-dependent kinase-5 activator 1 (CDK5R1) expression was significantly upregulated in all tested ES cells as compared to hMSCs. The overexpression of CDK5R1 led to the activation of CDK5, enabling the phosphorylation of retinoblastoma protein and persistent overexpression of CCNE. Moreover, miR-152 suppressed cell proliferation via cell cycle retardation, and its upregulation reduced tumor size and CCNE expression in tumor tissues. The overexpression of cyclin E (CCNE) has been detected in ES cells, but the detailed mechanisms have not been previously elucidated. These findings identify the miR152-CDK5R1 signaling axis as a critical mechanism for tumorigenesis that may serve as a new therapeutic target in Ewing's sarcoma. We believe that our results will aid in the development of effective treatment strategies for patients with ES.
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Affiliation(s)
- Masanori Kawano
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan
| | - Kazuhiro Tanaka
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
| | - Ichiro Itonaga
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan
| | - Tatsuya Iwasaki
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan
| | - Yuta Kubota
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan
| | - Hiroshi Tsumura
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan
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11
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Shoaib TH, Almogaddam MA, Andijani YS, Saib SA, Almaghrabi NM, Elyas AF, Azzouni RY, Awad EA, Mohamed SGA, Mohamed GA, Ibrahim SRM, Hussein HGA, Osman W, Ashour A, Sherif AE, Alzain AA. Marine-Derived Compounds for CDK5 Inhibition in Cancer: Integrating Multi-Stage Virtual Screening, MM/GBSA Analysis and Molecular Dynamics Investigations. Metabolites 2023; 13:1090. [PMID: 37887415 PMCID: PMC10608970 DOI: 10.3390/metabo13101090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/07/2023] [Accepted: 10/17/2023] [Indexed: 10/28/2023] Open
Abstract
Cyclin-dependent kinase 5 (CDK5) plays a crucial role in various biological processes, including immune response, insulin secretion regulation, apoptosis, DNA (deoxyribonucleic acid) damage response, epithelial-mesenchymal transition (EMT), cell migration and invasion, angiogenesis, and myogenesis. Overactivation of CDK5 is associated with the initiation and progression of cancer. Inhibiting CDK5 has shown potential in suppressing cancer development. Despite advancements in CDK5-targeted inhibitor research, the range of compounds available for clinical and preclinical trials remains limited. The marine environment has emerged as a prolific source of diverse natural products with noteworthy biological activities, including anti-cancer properties. In this study, we screened a library of 47,450 marine natural compounds from the comprehensive marine natural product database (CMNPD) to assess their binding affinity with CDK5. Marine compounds demonstrating superior binding affinity compared to a reference compound were identified through high-throughput virtual screening, standard precision and extra-precision Glide docking modes. Refinement of the selected molecules involved evaluating molecular mechanics-generalized born surface area (MM/GBSA) free binding energy. The three most promising compounds, (excoecariphenol B, excoecariphenol A, and zyzzyanone B), along with the reference, exhibiting favorable binding characteristics were chosen for molecular dynamics (MD) simulations for 200 nanoseconds. These compounds demonstrated interaction stability with the target during MD simulations. The marine compounds identified in this study hold potential as effective CDK5 inhibitors and warrant subsequent experimental validation.
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Affiliation(s)
- Tagyedeen H. Shoaib
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan; (T.H.S.); (M.A.A.)
| | - Mohammed A. Almogaddam
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan; (T.H.S.); (M.A.A.)
| | - Yusra Saleh Andijani
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah 30078, Saudi Arabia;
| | | | | | - Abdulaziz Fahad Elyas
- Emergency Medical Services Department, Madinah National Hospital, Madinah 11461, Saudi Arabia;
| | - Rahmah Yasin Azzouni
- King Faisal Specialist Hospital & Research Center, Al-Madinah Al-Munawwarah 42523, Saudi Arabia;
| | - Ehda Ahmad Awad
- Prince Mohammed Bin Abdulaziz Hospital-Al Madinah Al Munawarah-NGHA, Ministry of National Guard Health Affairs, Kingdom of Saudi Arabia, Riyadh 41511, Saudi Arabia;
| | - Shaimaa G. A. Mohamed
- Faculty of Dentistry, British University, El Sherouk City, Suez Desert Road, Cairo 11837, Egypt;
| | - Gamal A. Mohamed
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Sabrin R. M. Ibrahim
- Preparatory Year Program, Department of Chemistry, Batterjee Medical College, Jeddah 21442, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Hazem G. A. Hussein
- Preparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia;
| | - Wadah Osman
- Department of Pharmacognosy, Faculty of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi Arabia; (W.O.); (A.A.); (A.E.S.)
- Department of Pharmacognosy, Faculty of Pharmacy, University of Khartoum, Al-Qasr Ave., Khartoum 11111, Sudan
| | - Ahmed Ashour
- Department of Pharmacognosy, Faculty of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi Arabia; (W.O.); (A.A.); (A.E.S.)
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Asmaa E. Sherif
- Department of Pharmacognosy, Faculty of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi Arabia; (W.O.); (A.A.); (A.E.S.)
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Abdulrahim A. Alzain
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan; (T.H.S.); (M.A.A.)
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12
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Amin N, Wang H, Song Q, Bhaskar M, Yadav SP, Gilbert MR, Pant H, Tabouret E, Zhuang Z. TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal Carcinoma. Int J Mol Sci 2023; 24:11733. [PMID: 37511490 PMCID: PMC10380212 DOI: 10.3390/ijms241411733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/12/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Colorectal carcinoma (CRC) is a prevalent cancer worldwide with a high mortality rate. Evidence suggests that increased expression of Cyclin-dependent kinase 5 (CDK5) contributes to cancer progression, making it a promising target for treatment. This study examined the efficacy of selectively inhibiting CDK5 in colorectal carcinoma using TP5, a small peptide that selectively inhibits the aberrant and hyperactive CDK5/p25 complex while preserving physiological CDK5/p35 functions. We analyzed TP5's impact on CDK5 activity, cell survival, apoptosis, the cell cycle, DNA damage, ATM phosphorylation, and reactive oxygen species (ROS) signaling in mitochondria, in CRC cell lines, both alone and in combination with chemotherapy. We also assessed TP5's efficacy on a xenograft mouse model with HCT116 cells. Our results showed that TP5 decreased CDK5 activity, impaired cell viability and colony formation, induced apoptosis, increased DNA damage, and led to the G1 phase arrest of cell cycle progression. In combination with irinotecan, TP5 demonstrated a synergy by leading to the accumulation of DNA damage, increasing the γH2A.X foci number, and inhibiting G2/M arrest induced by Sn38 treatment. TP5 alone or in combination with irinotecan increased mitochondrial ROS levels and inhibited tumor growth, prolonging mouse survival in the CRC xenograft animal model. These results suggest that TP5, either alone or in combination with irinotecan, is a promising therapeutic option for colorectal carcinoma.
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Affiliation(s)
- Niranjana Amin
- National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA
| | - Herui Wang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Qi Song
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Manju Bhaskar
- Translational Neuroscience Center, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Mark R Gilbert
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Harish Pant
- National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA
| | - Emeline Tabouret
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Institute of NeuroPhysiopathology (INP), National Centre for Scientific Research (CNRS), Aix-Marseille University, 13005 Marseille, France
| | - Zhengping Zhuang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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13
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Karaś K, Karwaciak I, Chałaśkiewicz K, Sałkowska A, Pastwińska J, Bachorz RA, Ratajewski M. Anti-hepatocellular carcinoma activity of the cyclin-dependent kinase inhibitor AT7519. Biomed Pharmacother 2023; 164:115002. [PMID: 37311277 DOI: 10.1016/j.biopha.2023.115002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancerous tumors and one of the leading causes of death among cancer-related disorders. Chemotherapy is ineffective in HCC patients, and the number of drugs that are in use is limited. Thus, new molecules are needed that could increase the effectiveness of anti-HCC regimens. Here, we show that AT7519, a CDK inhibitor, exerts positive effects on HCC cells: it inhibits proliferation, migration and clonogenicity. Detailed analysis of the transcriptomes of cells treated with this compound indicated that AT7519 affects a substantial portion of genes that are associated with HCC development and progression. Moreover, we showed that the concomitant use of AT7519 with gefitinib or cabozantinib sensitized HCC cells to these drugs. Thus, our research indicates that AT7519 is worth considering in monotherapy for hepatocellular carcinoma patients or in combination with other drugs, e.g., gefitinib or cabozantinib.
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Affiliation(s)
- Kaja Karaś
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Iwona Karwaciak
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Katarzyna Chałaśkiewicz
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Anna Sałkowska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Joanna Pastwińska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Rafał A Bachorz
- Laboratory of Molecular Modeling, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland
| | - Marcin Ratajewski
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland.
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14
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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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15
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Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages. Nat Commun 2022; 13:2436. [PMID: 35508466 PMCID: PMC9068765 DOI: 10.1038/s41467-022-29960-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 04/09/2022] [Indexed: 12/13/2022] Open
Abstract
Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional and translational control, signaling transduction, and metabolism are dysregulated and differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β-catenin, AKT/mTOR and Notch pathways, cell cycle and DNA damage regulation. The targetable aurora kinase A and CDKs are upregulated. CTNNB1 and TP53 mutations are associated with altered protein phosphorylation related to actin filament organization and lipid metabolism, respectively. Integrative proteogenomic clusters show that HCC constitutes heterogeneous subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our study provides a comprehensive overview of the proteomic and phophoproteomic landscapes of HCCs, revealing the major pathways altered in the (phospho)proteome. Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated tumours and lacked information about the phosphoproteome. Here, the authors present a comprehensive HCC proteogenomics and phosphoproteomics study in patient samples from multiple etiologies and stages.
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16
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Li Y, Yao F, Jiao Z, Su X, Wu T, Peng J, Yang Z, Chen W, Yang A. Cyclin-dependent kinase 5 promotes the growth of tongue squamous cell carcinoma through the microRNA 513c-5p/cell division cycle 25B pathway and is associated with a poor prognosis. Cancer 2022; 128:1775-1786. [PMID: 35143052 PMCID: PMC9303762 DOI: 10.1002/cncr.34136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/01/2021] [Accepted: 01/05/2022] [Indexed: 12/26/2022]
Abstract
Background The objective of this study was to investigate the role and molecular mechanism of cyclin‐dependent kinase 5 (CDK5) in regulating the growth of tongue squamous cell carcinoma (TSCC). Methods The authors used multiple methods to detect the levels of CDK5 expression in samples of TSCC and to explore the relation between CDK5 expression and various clinicopathologic factors. In vivo and in vitro cell experiments were performed to detect the proliferation, invasion, and migration of TSCC cells with CDK5 knockdown or overexpression. These studies verified that CDK5 regulates the occurrence and development of TSCC cells through the microRNA 513c‐5p/cell division cycle 25B pathway. Results An elevated level of CDK5 expression in TSCC tissues was identified as an independent risk factor affecting TSCC growth and patient prognosis. Patients who had TSCC with low levels of CDK5 expression had a higher survival rate than those with high levels. Knockdown of CDK5 reduced the proliferation, migration, and invasion of TSCC cells both in vitro and in vivo. In addition, the authors observed that CDK5 regulated the growth of TSCC through the microRNA 513c‐5p/cell division cycle C25B pathway. Conclusions CDK5 functions as an oncogene in TSCC and might serve as a molecular marker for use in the diagnosis and treatment of TSCC. Lay Summary
Tongue squamous cell carcinoma (TSCC) is 1 of the most common malignant tumors of the head and neck, and the survival rate of patients with tongue cancer has been very low. Therefore, it is important to study the molecular mechanism of TSCC progression to identify biomarkers that can be used to improve its clinical diagnosis and treatment. Cyclin‐dependent kinase 5 (CDK5) is an atypical member of the cyclin‐dependent kinase family and is involved in regulating the cell cycle. Changes in the cell cycle are of great significance for the occurrence and development of tumor cells; and, in recent years, increasing evidence has suggested that CDK5 exists in a disordered state in cancer cells. In this study, the authors demonstrate that CDK5 functions as an oncogene in TSCC and might serve as a molecular marker for use in the diagnosis and treatment of TSCC. The role of cyclin‐dependent kinase 5 and its molecular mechanism in regulating the growth of tongue squamous cell carcinoma (TSCC) are investigated. The results indicate that cyclin‐dependent kinase 5 is involved in the occurrence and development of TSCC and could possibly serve as a new prognostic marker and molecular target for treating TSCC.
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Affiliation(s)
- Yixuan Li
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Fan Yao
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Zan Jiao
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Xuan Su
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Tong Wu
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Jin Peng
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Zhongyuan Yang
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Weichao Chen
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
| | - Ankui Yang
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China
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17
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The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage. Proc Natl Acad Sci U S A 2021; 118:2112674118. [PMID: 34795058 DOI: 10.1073/pnas.2112674118] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2021] [Indexed: 01/12/2023] Open
Abstract
High expression of programmed death-ligand 1 (PD-L1) in cancer cells drives immune-independent, cell-intrinsic functions, leading to resistance to DNA-damaging therapies. We find that high expression of the ubiquitin E3 ligase FBXO22 sensitizes nonsmall cell lung cancer (NSCLC) cells to ionizing radiation (IR) and cisplatin, and that activation of FBXO22 by phosphorylation is necessary for this function. Importantly, FBXO22 activates PD-L1 ubiquitination and degradation, which in turn increases the sensitivity of NSCLC cells to DNA damage. Cyclin-dependent kinase 5 (CDK5), aberrantly active in cancer cells, plays a crucial role in increasing the expression of PD-L1 in medulloblastoma [R. D. Dorand et al, Science 353, 399-403 (2016)]. We show in NSCLC cells that inhibiting CDK5 or reducing its expression increases the level of FBXO22, decreases that of PD-L1, and increases the sensitivity of the cells to DNA damage. We conclude that FBXO22 is a substrate of CDK5, and that inhibiting CDK5 reduces PD-L1 indirectly by increasing FBXO22. Pairing inhibitors of CDK5 with immune checkpoint inhibitors may increase the efficacy of immune checkpoint blockade alone or in combination with DNA-damaging therapies.
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18
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CircETFA upregulates CCL5 by sponging miR-612 and recruiting EIF4A3 to promote hepatocellular carcinoma. Cell Death Discov 2021; 7:321. [PMID: 34716323 PMCID: PMC8556257 DOI: 10.1038/s41420-021-00710-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/24/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022] Open
Abstract
As a kind of malignant tumors, hepatocellular carcinoma (HCC) has been studied continuously, but the mechanisms are not well understood. Circular RNAs (circRNAs) are widespread in eukaryotes and play an important role in the growth of organisms and in the occurrence of diseases. The role of circRNAs in HCC remains to be further explored. In this study, CircRNA microarray analysis was used to assess the plasma from HCC patients and healthy controls and to identify circRNAs involved in HCC tumorigenesis. CircETFA was overexpressed in HCC tissues, plasma, and cells. Clinicopathological data revealed that abnormally high circETFA expression was associated with a poor prognosis. In function, circETFA promotes the malignant phenotype of HCC cells in vivo and in vitro, inhibits cycle arrest, and decreases the proportion of apoptotic cells. In mechanism, it can upregulate C-C motif chemokine ligand 5 (CCL5) in HCC cells, thereby regulating the phosphoinositide 3-kinase (PI3K)/Akt pathway and other key downstream effectors (e.g., FoxO6). Furthermore, circETFA prolonged the half-life of CCL5 mRNA by recruiting the eukaryotic initiation factor 4A3 (EIF4A3) and acted as a sponge of hsa-miR-612 to suppress the silencing effect of hsa-miR-612 on CCL5. In conclusion, CircETFA can increase the expression of CCL5 to promote the progression of HCC by sponging hsa-mir-612 and recruiting EIF4A3, and is promising as a novel biomarker and therapeutic target.
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The cyclin dependent kinase inhibitor Roscovitine prevents diet-induced metabolic disruption in obese mice. Sci Rep 2021; 11:20365. [PMID: 34645915 PMCID: PMC8514475 DOI: 10.1038/s41598-021-99871-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/28/2021] [Indexed: 12/16/2022] Open
Abstract
Most strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. Treatment of obese individuals will require therapies that reverse the detrimental effects of excess body weight. Cyclin-dependent kinases have been shown to contribute to obesity and its adverse complications. Here, we show that roscovitine; a an orally available cyclin-dependent kinase inhibitor; given to male mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that roscovitine suppressed expression of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. It also identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases, AGC kinases and CAMK kinases. Pathway enrichment analysis showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and creatine biosynthesis are enriched following roscovitine treatment. For brown adipose tissue (BAT), analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups, AGC and CMGC kinases. Among the top enriched pathways were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling. We conclude that roscovitine is effective at preventing prolonged diet-induced metabolic disruption and restoring mitochondrial activity in BAT and eWAT.
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Wu J, Tan Z, Li H, Lin M, Jiang Y, Liang L, Ma Q, Gou J, Ning L, Li X, Guan F. Melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O-GlcNAcylation of cyclin-dependent-like kinase 5. J Pineal Res 2021; 71:e12765. [PMID: 34487576 DOI: 10.1111/jpi.12765] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/13/2021] [Accepted: 09/03/2021] [Indexed: 11/29/2022]
Abstract
Melatonin helps to maintain circadian rhythm, exerts anticancer activity, and plays key roles in regulation of glucose homeostasis and energy metabolism. Glycosylation, a form of metabolic flux from glucose or other monosaccharides, is a common post-translational modification. Dysregulated glycosylation, particularly O-GlcNAcylation, is often a biomarker of cancer cells. In this study, elevated O-GlcNAc level in bladder cancer was inhibited by melatonin treatment. Melatonin treatment inhibited proliferation and migration and enhanced apoptosis of bladder cancer cells. Proteomic analysis revealed reduction in cyclin-dependent-like kinase 5 (CDK5) expression by melatonin. O-GlcNAc modification determined the conformation of critical T-loop domain on CDK5 and further influenced the CDK5 stability. The mechanism whereby melatonin suppressed O-GlcNAc level was based on decreased glucose uptake and metabolic flux from glucose to UDP-GlcNAc, and consequent reduction in CDK5 expression. Melatonin treatment, inhibition of O-GlcNAcylation by OSMI-1, or mutation of key O-GlcNAc site strongly suppressed in vivo tumor growth. Our findings indicate that melatonin reduces proliferation and promotes apoptosis of bladder cancer cells by suppressing O-GlcNAcylation of CDK5.
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Affiliation(s)
- Jinpeng Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Zengqi Tan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Hongjiao Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Meixuan Lin
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | | | - Liang Liang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qilong Ma
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Junjie Gou
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
| | - Lulu Ning
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an, China
| | - Xiang Li
- Institute of Hematology, School of Medicine, Northwest University, Xi'an, China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, China
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21
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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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22
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Chen Y, Xie H, Xie T, Yang X, Pang Y, Ye S. Elevated Expression of PDZD11 Is Associated With Poor Prognosis and Immune Infiltrates in Hepatocellular Carcinoma. Front Genet 2021; 12:669928. [PMID: 34093661 PMCID: PMC8176286 DOI: 10.3389/fgene.2021.669928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/30/2021] [Indexed: 01/11/2023] Open
Abstract
Epithelial cells are held together by tight and adherent junctions, which are destroyed by the activation of epithelial-to-mesenchymal transition (EMT). The PLEKHA7-PDZD11 complex has been reported to be important for epithelial cell adhesion and connecting tissues. However, there is no research regarding the expression and role of PDZD11 in liver hepatocellular carcinoma (LIHC) progression. Here, we analyzed PDZD11 mRNA expression and its clinical results in LIHC patient RNA sequencing data based on different open databases. Furthermore, we examined differences in PDZD11 expression in LIHC tissues and cell lines using western blotting and real-time qPCR. These results are the first to report that the mRNA and protein levels of PDZD11 are significantly overexpressed in LIHC. Moreover, high expression of PDZD11 was correlated with poor overall survival in patients with LIHC. Gene regulatory network analysis suggested that PDZD11 is mainly involved in copper ion homeostasis, proteasome, and oxidative phosphorylation pathways. Interestingly, we found that PDZD11 levels were positively correlated with the abundance of immune infiltrates. In particular, higher infiltration levels of CD4+ T cells and macrophage subsets significantly affected LIHC patient prognosis. Taken together, these results demonstrate that PDZD11 could be a potential diagnostic and prognostic biomarker in LIHC.
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Affiliation(s)
- Yao Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haifeng Xie
- Hangzhou Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Ting Xie
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xunjun Yang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.,Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yilin Pang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - SongDao Ye
- Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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Elevated CDK5R1 predicts worse prognosis in hepatocellular carcinoma based on TCGA data. Biosci Rep 2021; 41:227408. [PMID: 33346796 PMCID: PMC7791553 DOI: 10.1042/bsr20203594] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a malignant tumor with rapid progression, high recurrence rate and poor prognosis. The objective of our investigation was to explore the prognostic value of CDK5R1 in HCC. Methods: The raw data of HCC raw data were downloaded from The Cancer Genome Atlas (TCGA) database. The Wilcoxon signed-rank test, Kruskal–Wallis test and logistic regression were applied to investigate the relevance between the CDK5R1 expression and clinicopathologic characteristics in HCC. Kaplan–Meier and Cox regression analysis were employed to examine the association between clinicopathologic features and survival. Gene set enrichment analysis (GSEA) was applied to annotate the biological function of CDK5R1. Results: CDK5R1 was highly expressed in HCC tissues. The high expression of CDK5R1 in HCC tissues was significantly associated with tumor status (P=0.00), new tumor event (P=0.00), clinical stage (P=0.00) and topography (P=0.00). Elevated CDK5R1 had significant correlation with worse overall survival (OS; P=7.414e−04), disease-specific survival (DSS; P=5.642e−04), disease-free interval (DFI; P=1.785e−05) and progression-free interval (PFI; P=2.512e−06). Besides, univariate and multivariate Cox regression analysis uncovered that increased CDK5R1 can independently predict adverse OS (P=0.037, hazard ratio [HR]= 1.7 (95% CI [1.0–2.7])), DFI (P=0.007, hazard ratio [HR]= 3.0 (95% CI [1.4–6.7])), PFI (P=0.007, hazard ratio [HR]= 2.8 (95% CI [1.3–5.9])). GSEA disclosed that notch signaling pathway and non-small cell lung cancer were prominently enriched in CDK5R1 high expression phenotype. Conclusions: Increased CDK5R1 may act as a promising independent prognostic factor of poor survival in HCC.
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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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25
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Guo JC, Yang YJ, Guo M, Zhang JQ, Zheng JF, Liu Z. Involvement of CDK11B-mediated SPDEF ubiquitination and SPDEF-mediated microRNA-448 activation in the oncogenicity and self-renewal of hepatocellular carcinoma stem cells. Cancer Gene Ther 2020; 28:1136-1149. [PMID: 33328586 DOI: 10.1038/s41417-020-00261-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 10/25/2020] [Accepted: 11/10/2020] [Indexed: 11/09/2022]
Abstract
Increasing evidence has suggested the crucial role cyclin-dependent kinases (CDKs) in the biology of hepatocellular carcinoma (HCC), a lethal malignancy with high morbidity and mortality. Hence, this study explored the modulatory effect of the putative cyclin-dependent kinase 11B (CDK11B)-mediated ubiquitination on HCC stem cells. The expression of CDK11B, SAM pointed domain-containing ETS transcription factor (SPDEF) and DOT1-like histone lysine methyltransferase (DOT1L) was determined by RT-qPCR and western blot analysis in HCC tissues and cells. The interaction among CDK11B, SPDEF, miR-448, and DOT1L was analyzed by Co-IP, ubiquitination-IP and ChIP assays, whereas their effects on the biological characteristics of HCC stem cells were assessed by sphere formation and colony formation assays. An in vivo xenograft tumor model was developed for validating the regulation of CDK11B in oncogenicity of HCC stem cells. We characterized the aberrant upregulation of CDK11B and downregulation SPDEF in HCC tissues and cells. CDK11B degraded SPDEF through ubiquitin-proteasome pathway, whereas SPDEF could bind to the miR-448 promoter and inhibit the expression of DOT1L by activating miR-448, whereby promoting self-renewal of HCC stem cells. Knockdown of CDK11B attenuated the self-renewal capability of HCC stem cells and their oncogenicity in vivo. These findings highlighted that blocking the CDK11B-induced degradation of SPDEF and enhancing miR-448-dependent inhibition of DOT1L may delay the progression of HCC by restraining self-renewal capability of HCC stem cells, representing novel targets for HCC management.
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Affiliation(s)
- Jun-Cheng Guo
- Department of Hepatobiliary Surgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, P. R. China
| | - Yi-Jun Yang
- Department of Hepatobiliary Surgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, P. R. China.
| | - Min Guo
- Psychological Research Center, Hainan General Hospital, Haikou, 570311, P. R. China
| | - Jian-Quan Zhang
- Department of Hepatobiliary Surgery, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570208, P. R. China.
| | - Jin-Fang Zheng
- Department of Hepatobiliary Surgery, Hainan General Hospital, Haikou, 570311, P. R. China
| | - Zhuo Liu
- School of Public Health, Hainan Medical University, Haikou, 571199, P. R. China
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26
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Papin S, Paganetti P. Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer. Brain Sci 2020; 10:brainsci10110862. [PMID: 33207722 PMCID: PMC7696480 DOI: 10.3390/brainsci10110862] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022] Open
Abstract
Neurodegenerative disorders and cancer may appear unrelated illnesses. Yet, epidemiologic studies indicate an inverse correlation between their respective incidences for specific cancers. Possibly explaining these findings, increasing evidence indicates that common molecular pathways are involved, often in opposite manner, in the pathogenesis of both disease families. Genetic mutations in the MAPT gene encoding for TAU protein cause an inherited form of frontotemporal dementia, a neurodegenerative disorder, but also increase the risk of developing cancer. Assigning TAU at the interface between cancer and neurodegenerative disorders, two major aging-linked disease families, offers a possible clue for the epidemiological observation inversely correlating these human illnesses. In addition, the expression level of TAU is recognized as a prognostic marker for cancer, as well as a modifier of cancer resistance to chemotherapy. Because of its microtubule-binding properties, TAU may interfere with the mechanism of action of taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network and impair cell division. Indeed, a low TAU expression is associated to a better response to taxanes. Although TAU main binding partners are microtubules, TAU is able to relocate to subcellular sites devoid of microtubules and is also able to bind to cancer-linked proteins, suggesting a role of TAU in modulating microtubule-independent cellular pathways associated to oncogenesis. This concept is strengthened by experimental evidence linking TAU to P53 signaling, DNA stability and protection, processes that protect against cancer. This review aims at collecting literature data supporting the association between TAU and cancer. We will first summarize the evidence linking neurodegenerative disorders and cancer, then published data supporting a role of TAU as a modifier of the efficacy of chemotherapies and of the oncogenic process. We will finish by addressing from a mechanistic point of view the role of TAU in de-regulating critical cancer pathways, including the interaction of TAU with cancer-associated proteins.
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Affiliation(s)
- Stéphanie Papin
- Neurodegeneration Research Group, Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Via ai Söi 24, CH-6807 Torricella-Taverne, Switzerland;
| | - Paolo Paganetti
- Neurodegeneration Research Group, Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale, Via ai Söi 24, CH-6807 Torricella-Taverne, Switzerland;
- Faculty of Biomedical Neurosciences, Università della Svizzera Italiana, CH-6900 Lugano, Switzerland
- Correspondence: ; Tel.: +41-91-811-7250
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Zeng Y, Liu Q, Wang Y, Tian C, Yang Q, Zhao Y, Liu L, Wu G, Xu S. CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer. Int J Radiat Oncol Biol Phys 2020; 108:758-769. [PMID: 32407930 DOI: 10.1016/j.ijrobp.2020.05.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/17/2020] [Accepted: 05/01/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE Tumor resistance to radiation therapy is a therapeutic challenge in the treatment of patients with non-small cell lung cancer. Cyclin-dependent kinase 5 (CDK5) has been proposed to participate in cell proliferation, migration and invasion, drug resistance, and immune evasion. However, the functions and regulatory mechanisms of CDK5 in lung cancer radioresistance have not been investigated. METHODS AND MATERIALS DNA damage response and repair were measured by neutral comet assay and γ-H2AX and Rad51 foci staining. The biological functions of CDK5 in lung cancer radioresistance were investigated with clonogenic survival assays and xenograft tumor models. Small interfering RNAs and short hairpin RNAs were used to knock down CDK5 in A549 and H1299 cells. The effects of CDK5 depletion on the tumorigenic behaviors of lung cancer cells were evaluated in vitro and in vivo. Gene expression was examined by RNA-seq and quantitative real-time polymerase chain reaction. RESULTS We report that CDK5 depletion impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we identify TAZ, a component of the Hippo pathway, as a critical downstream effector of CDK5. Loss of CDK5 downregulates TAZ expression and attenuates Hippo signaling activation. Importantly, we provide evidence that TAZ is the major effector mediating the biological functions of CDK5 in lung cancer. CONCLUSIONS These results illustrate that CDK5 activates Hippo signaling via TAZ to participate in tumorigenesis and radioresistance, suggesting that CDK5 may be a promising radiosensitization target for the treatment of lung cancer.
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Affiliation(s)
- Yulan Zeng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Quan Liu
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ye Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Tian
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qifan Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ye Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Gang Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Shuangbing Xu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma. Cancers (Basel) 2020; 12:cancers12071935. [PMID: 32708903 PMCID: PMC7409269 DOI: 10.3390/cancers12071935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/13/2020] [Indexed: 11/17/2022] Open
Abstract
We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma.
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29
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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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Tang H, Xu L, Cen X, Yang L, Feng J, Li G, Zhu H, Gao S, Yu Y, Zhao Y, Tian Z, Hou L, Yu S, Gao G. CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance. Int J Mol Med 2020; 45:1661-1672. [PMID: 32236619 PMCID: PMC7169959 DOI: 10.3892/ijmm.2020.4553] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022] Open
Abstract
The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (CDK) family, CDK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this study is to investigate the effects of CDK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells. In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti-myeloma activity accompanied by inhibiting the activation of the nuclear factor-κB pathway. This study demonstrates the important role of CDK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.
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Affiliation(s)
- Hailong Tang
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Li Xu
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Xi Cen
- Department of Public Health Sciences, University of Rochester, Rochester, NY 14642, USA
| | - Li Yang
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Juan Feng
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Guang Li
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Huafeng Zhu
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Shan Gao
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yan Yu
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yaping Zhao
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Zhiqiang Tian
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Liping Hou
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Shuchun Yu
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Guangxun Gao
- Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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Cervello M, Emma MR, Augello G, Cusimano A, Giannitrapani L, Soresi M, Akula SM, Abrams SL, Steelman LS, Gulino A, Belmonte B, Montalto G, McCubrey JA. New landscapes and horizons in hepatocellular carcinoma therapy. Aging (Albany NY) 2020; 12:3053-3094. [PMID: 32018226 PMCID: PMC7041742 DOI: 10.18632/aging.102777] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 01/12/2020] [Indexed: 04/12/2023]
Abstract
Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient.
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Affiliation(s)
- Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Maria R. Emma
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Lydia Giannitrapani
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maurizio Soresi
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Shaw M. Akula
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Stephen L. Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Linda S. Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Alessandro Gulino
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Beatrice Belmonte
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
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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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33
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Shen S, Dean DC, Yu Z, Duan Z. Role of cyclin-dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway. Hepatol Res 2019; 49:1097-1108. [PMID: 31009153 DOI: 10.1111/hepr.13353] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 02/23/2019] [Accepted: 03/28/2019] [Indexed: 12/12/2022]
Abstract
Liver cancer is the fourth leading cause of cancer related mortality in the world, with hepatocellular carcinoma (HCC) representing the most common primary subtype. Two-thirds of HCC patients have advanced disease when diagnosed, and for these patients, treatment strategies remain limited. In addition, there is a high incidence of tumor recurrence after surgical resection with the current treatment regimens. The development of novel and more effective agents is required. Cyclin-dependent kinases (CDKs) constitute a family of 21 different protein kinases involved in regulating cell proliferation, apoptosis, and drug resistance, and are evaluated in preclinical and clinical trials as chemotherapeutics. To summarize and discuss the therapeutic potential of targeting CDKs in HCC, recent published articles identified from PubMed were comprehensively reviewed. The key words included hepatocellular carcinoma, cyclin-dependent kinases, and CDK inhibitors. This review focuses on the emerging evidence from studies describing the genetic and functional aspects of CDKs in HCC. We also present an overview of CDK inhibitors that have shown efficacy in laboratory studies of HCC. Although many of the studies assessing CDK-targeting therapies in HCC are at the preclinical stage, there is significant evidence that CDK inhibitors used alone or in combination with established chemotherapy drugs could have significant applications in HCC.
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Affiliation(s)
- Shen Shen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Sarcoma Biology Laboratory, Department of Orthopedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, USA
| | - Dylan C Dean
- Sarcoma Biology Laboratory, Department of Orthopedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, USA
| | - Zujiang Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenfeng Duan
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Sarcoma Biology Laboratory, Department of Orthopedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, USA
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Shao YY, Li YS, Hsu HW, Lin H, Wang HY, Wo RR, Cheng AL, Hsu CH. Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11101433. [PMID: 31561409 PMCID: PMC6827105 DOI: 10.3390/cancers11101433] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 09/19/2019] [Indexed: 12/18/2022] Open
Abstract
Alterations in cell cycle regulators are common in hepatocellular carcinoma (HCC). We tested the efficacy of composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib on HCC. In vitro, dinaciclib exhibited potent antiproliferative activities in HCC cell lines regardless of Rb or c-myc expression levels. Dinaciclib significantly downregulated the phosphorylation of Rb (target of CDKs 1 and 2), ataxia telangiectasia mutated kinase (target of CDK5), and RNA polymerase II (target of CDK9) in the HCC cells. In xenograft studies, mice receiving dinaciclib tolerated the treatment well without significant body weight changes and exhibited a significantly slower tumor growth rate than the mice receiving vehicles. RNA interference (RNAi) of CDKs 1 and 9 was more effective in inhibiting the cell proliferation of HCC cells than RNAi of CDKs 2 and 5. Overexpression of CDK9 significantly reduced the efficacy of dinaciclib in HCC cells, but overexpression of CDK1 did not. In conclusion, composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib exhibited potent in vitro and in vivo activity against HCC. CDK9 inhibition might be the crucial mechanism.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Yong-Shi Li
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Hung-Wei Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Hang Lin
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Han-Yu Wang
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Rita Robin Wo
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
- Department of Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
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Zheng XF, Acharya SS, Choe KN, Nikhil K, Adelmant G, Satapathy SR, Sharma S, Viccaro K, Rana S, Natarajan A, Sicinski P, Marto JA, Shah K, Chowdhury D. A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1. Nat Commun 2019; 10:4252. [PMID: 31534152 PMCID: PMC6751209 DOI: 10.1038/s41467-019-12084-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 08/20/2019] [Indexed: 01/10/2023] Open
Abstract
Mitotic cells attenuate the DNA damage response (DDR) by phosphorylating 53BP1, a critical DDR mediator, to prevent its localization to damaged chromatin. Timely dephosphorylation of 53BP1 is critical for genome integrity, as premature recruitment of 53BP1 to DNA lesions impairs mitotic fidelity. Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis to allow its recruitment to DNA lesions in G1. How cells appropriately dephosphorylate 53BP1, thereby restoring DDR, is unclear. Here, we elucidate the underlying mechanism of kinetic control of 53BP1 dephosphorylation in mitosis. We demonstrate that CDK5, a kinase primarily functional in post-mitotic neurons, is active in late mitotic phases in non-neuronal cells and directly phosphorylates PP4R3β, the PP4 regulatory subunit that recognizes 53BP1. Specific inhibition of CDK5 in mitosis abrogates PP4R3β phosphorylation and abolishes its recognition and dephosphorylation of 53BP1, ultimately preventing the localization of 53BP1 to damaged chromatin. Our results establish CDK5 as a regulator of 53BP1 recruitment.
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Affiliation(s)
- Xiao-Feng Zheng
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA
| | - Sanket S Acharya
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA
| | - Katherine N Choe
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA
| | - Kumar Nikhil
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Guillaume Adelmant
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Shakti Ranjan Satapathy
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Samanta Sharma
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Keith Viccaro
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Sandeep Rana
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Amarnath Natarajan
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Peter Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Jarrod A Marto
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
| | - Kavita Shah
- Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Dipanjan Chowdhury
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
- Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
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Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res 2019; 38:396. [PMID: 31500650 PMCID: PMC6734524 DOI: 10.1186/s13046-019-1396-4] [Citation(s) in RCA: 297] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.
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MESH Headings
- Adaptive Immunity
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Biomarkers, Tumor
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Clinical Trials as Topic
- Combined Modality Therapy/methods
- Humans
- Immunity, Innate
- Immunotherapy/adverse effects
- Immunotherapy/methods
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Translational Research, Biomedical
- Treatment Outcome
- Tumor Microenvironment/immunology
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Affiliation(s)
- Yaojie Fu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shanshan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
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Zhang X, Wang J, Jia Y, Liu T, Wang M, Lv W, Zhang R, Shi J, Liu L. CDK5 neutralizes the tumor suppressing effect of BIN1 via mediating phosphorylation of c-MYC at Ser-62 site in NSCLC. Cancer Cell Int 2019; 19:226. [PMID: 31496920 PMCID: PMC6720419 DOI: 10.1186/s12935-019-0952-5] [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: 07/05/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Background Bridging integrator 1 (BIN1) has showed outstanding tumor-suppressive potential via inhibiting c-MYC-mediated tumorigenesis. However, a frequent phosphorylation of c-MYC at Ser-62 site could block the BIN1/c-MYC interaction and limits the tumor-suppressive effect of BIN1. Cyclin-dependent kinase 5 (CDK5), a generally dysregulated protein in various carcinomas, can mediate c-MYC phosphorylation at Ser-62 site. However, whether the existence of CDK5 could block the BIN1/c-MYC interaction remains unclear. Materials and methods The expression of CDK5 and BIN1 in non-small cell lung cancer (NSCLC) cell lines were measured. CDK5 was knocked down and overexpressed in H460 and PC9 cells, respectively. CCK-8, wound healing and transwell were used to detect the proliferation, migration and invasion ability of NSCLC cells. Tumor-bearing nude mouse model was built with H460 cells. Dinaciclib was added to realize the effect of CDK5 inhibition in vivo. NSCLC and matched para-carcinoma specimens were collected from 153 patients who underwent radical operation. IHC was performed to determine the expression of CDK5 in the specimens. Kaplan–Meier analysis was used to analyze the correlation between the postoperative survival and CDK5 expression. Results CDK5 was highly expressed in H460 cells, and knockdown of CDK5 could restore the BIN1/c-MYC interaction. Meanwhile, low expression of CDK5 was observed in PC9 cells, and overexpression of CDK5 blocked the BIN1/c-MYC interaction. Consequently, the growth, migration, invasion and epithelial mesenchymal transition (EMT) ability of H460 and PC9 cells could be facilitated by CDK5. The addition of CDK5 inhibitor Dinaciclib significantly suppressed the tumorigenesis ability of NSCLC cells in tumor-bearing mouse model. Furthermore, high expression of CDK5, along with low expression of BIN1, could predict poor postoperative prognosis of NSCLC patients. The patients with high expression of CDK5 and low expression of BIN1 showed similar prognosis, indicating that CDK5 could neutralize the tumor suppressing effect of BIN1 in clinical situation. Conclusions CDK5 blocked the interaction of BIN1 and c-MYC via promoting phosphorylation of c-MYC at ser-62 site, ultimately facilitated the progression of NSCLC.
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Affiliation(s)
- Xiangyu Zhang
- 1Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang, China
| | - Jiali Wang
- 1Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang, China
| | - Yunlong Jia
- 1Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang, China
| | - Tianxu Liu
- 1Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang, China
| | - Mengjie Wang
- 1Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang, China
| | - Wei Lv
- 1Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang, China
| | - Rong Zhang
- 2Department of Toxicology, Hebei Medical University, Shijiazhuang, China
| | - Juan Shi
- 3State Key Laboratory of Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lihua Liu
- 1Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang, China
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MicroRNA-505-5p functions as a tumor suppressor by targeting cyclin-dependent kinase 5 in cervical cancer. Biosci Rep 2019; 39:BSR20191221. [PMID: 31266812 PMCID: PMC6658724 DOI: 10.1042/bsr20191221] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/19/2019] [Accepted: 07/02/2019] [Indexed: 12/28/2022] Open
Abstract
MicroRNAs (miRs) are considered to be tumor suppressors or oncogenes as they regulate cell proliferation, migration, invasion, and differentiation. Recently, microRNA-505 (miR-505) has been reported as being involved in the progression of several human cancers. In the present study, we aim to investigate the expression rate and functional role of miR-505-5p in cervical cancer (CC) to determine its significance regarding the disease’s development. The expression of miR-505-5p and cyclin-dependent kinase 5 (CDK5) in specimens of patients with CC and CC cell lines was examined by quantitative real-time PCR (qRT-PCR) and Western Blot. The relationship between miR-505-5p and CDK5 was verified by luciferase reporter assay. Cell counting kit-8 (CCK-8) assay, Scratch wound healing assay and transwell assay were used to detect the roles of miR-505-5p and CDK5 in CC cell functions. Western Blot was utilized to explore the epithelial–mesenchymal transition (EMT) markers. The result showed that in CC tissues and CC cell lines miR-505-5p was down-regulated while CDK5 level was up-regulated. MiR-505-5p was closely correlated with the metastasis-associated clinicopathological features. Overexpression of miR-505-5p inhibited cell viability, cell metastasis and EMT in CC cells. CDK5 was confirmed as a direct target of miR-505-5p and inverse relationship between them was also observed. Overexpression of CDK5 reduces the inhibitory effects of miR-505-5p in CC. Taken together, these results determine that miR-505-5p is a tumor suppressor miRNA which regulates tumor cell proliferation, migration, and invasion via binding to the functional target CDK5 and demonstrates its potential for future use in the treatment of CC.
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Zhu L, Ding R, Zhang J, Zhang J, Lin Z. Cyclin-dependent kinase 5 acts as a promising biomarker in clear cell Renal Cell Carcinoma. BMC Cancer 2019; 19:698. [PMID: 31311512 PMCID: PMC6636025 DOI: 10.1186/s12885-019-5905-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/02/2019] [Indexed: 02/06/2023] Open
Abstract
Background This research provides the first evidence of CDK5 in ccRCC prognosis and correlation with different p21 expression in overall survival (OS) analysis. Methods The data from both of The Cancer Genome Atlas (TCGA) and Gene Expression of Normal and Tumor Tissue (GENT) were analyzed for determining the expression of CDK5 in kidney cancer. Tissue microarray that made by using 150 ccRCC samples was used in immunohistochemistry (IHC) analysis. A validation of OS cohort was extracted from Oncomine database. Results The CDK5 expression was significantly lower in cancer tissue compared with normal in TCGA (p < 0.0001), GENT database also showed a relative low expression in kidney cancer. Among 150 ccRCC patients, low CDK5 was detected in 83 cases (55.3%), low p21 in 97 cases (64.7%). CDK5 was associated with the advanced TNM stage (p = 0.042), and Fuhrman grade (p = 0.035). Patients with lower CDK5 might be more likely to be aggressive status. According to the combination analysis of CDK5 and p21, patients in CDK5 low/p21 low group showed poorer survival rate, and no significant survival difference was observed in other groups. In the Cox multivariate analysis, the co-expression of CDK5 low/p21 low was identified as an independent prognostic factor in ccRCC patients. Conclusions Together, our findings provided the first evidence that CDK5 was acting as a promising biomarker in ccRCC patients, and co-expression of CDK5 and p21 is an independent prognostic for overall survival. IHC analysis of CDK5 and p21 on cancer tissues after surgery may help to evaluate and predict the outcome of ccRCC patients. Electronic supplementary material The online version of this article (10.1186/s12885-019-5905-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Liangsong Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Rong Ding
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianping Zhang
- Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China
| | - Jin Zhang
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, 1630 Dong Fang Road, Shanghai, China.
| | - Zongming Lin
- Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China.
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Wang F, Zhao W, Gao Y, Zhou J, Li H, Zhang G, Guo D, Xie C, Li J, Yin Z, Zhang J. CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:286. [PMID: 31272499 PMCID: PMC6610961 DOI: 10.1186/s13046-019-1297-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 06/26/2019] [Indexed: 01/06/2023]
Abstract
Background CDK5, an atypical member of the CDK family, play a significant role in the tumorigenesis of multiple organ, but CDK5 and its substrates in genesis and development of HCC is still unclear. Methods Expression of CDK5 in HCC tumor and paired adjacent noncancerous tissues from 90 patients were measured by Western blotting, immunohistochemistry, and real-time PCR. The role of CDK5 in cell function and tumorigenesis was explored in HCC cell lines, ex vivo xenografts and diethylnitrosamine induced HCC model. Furthermore, comparative phosphoproteomic screening identified the oncoprotein TPX2 as a new substrate of CDK5. We also identified the effect of CDK5/P25 interaction blocker tamoxifen on HCC cell growth and migration. Results CDK5 was increased in HCC tisues and the level of CDK5 was correlated with the severity of HCC based on patient recurrence and 5-year fatality rate. Exogenously expressed CDK5 but not kinase-dead CDK5 promoted proliferation, migration, and invasion of HCC cells. Functional ablation of CDK5 significantly inhibited the exacerbation of HCC cells. Xenograft implantation of HCC cells overexpressing CDK5 promoted tumorigenesis, and genetic knockdown of CDK5 reduced HCC growth and metastasis in vivo. More importantly, heterozygous knockout CDK5 (Cdk5+/−) attenuated HCC tumorigenesis induced by diethylnitrosamine. CDK5-mediated phosphorylation of TPX2 at serine 486 promoted its protein stability. TPX2 silence could restore HCC cell migration capability with overexpression CDK5. Treatment with tamoxifen inhibited cell growth and migration of HCC, demonstrating the role of active CDK5 in HCC. Conclusions Our results suggest activation of CDK5 is associated with HCC tumorigenesis. CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular proliferation and tumorigenicity. Electronic supplementary material The online version of this article (10.1186/s13046-019-1297-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fuqiang Wang
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, 361004, Fujian, China
| | - Wenxing Zhao
- Taian City Central Hospital, Taian, 271000, Shandong, China
| | - Yuehong Gao
- Fujian Provincial Key Laboratory of Neurodegenerative Diseaseand Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
| | - Jiechao Zhou
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Huifang Li
- Fujian Provincial Key Laboratory of Neurodegenerative Diseaseand Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
| | - Guanyun Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Diseaseand Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
| | - Dong Guo
- Fujian Provincial Key Laboratory of Neurodegenerative Diseaseand Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
| | - Chengrong Xie
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, 361004, Fujian, China
| | - Jie Li
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, 361004, Fujian, China
| | - Zhenyu Yin
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, 361004, Fujian, China.
| | - Jie Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Diseaseand Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China.
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Khair N, Lenjisa JL, Tadesse S, Kumarasiri M, Basnet SKC, Mekonnen LB, Li M, Diab S, Sykes MJ, Albrecht H, Milne R, Wang S. Discovery of CDK5 Inhibitors through Structure-Guided Approach. ACS Med Chem Lett 2019; 10:786-791. [PMID: 31098000 PMCID: PMC6511963 DOI: 10.1021/acsmedchemlett.9b00029] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/20/2019] [Indexed: 12/18/2022] Open
Abstract
Specific abrogation of cyclin-dependent kinase 5 (CDK5) activity has been validated as a viable approach for the development of anticancer agents. However, no selective CDK5 inhibitor has been reported to date. Herein, a structure-based in silico screening was employed to identify novel scaffolds from a library of compounds to identify potential CDK5 inhibitors that would be relevant for drug discovery. Hits, representatives of three chemical classes, were identified as inhibitors of CDK5. Structural modification of hit-1 resulted in 29 and 30. Compound 29 is a dual inhibitor of CDK5 and CDK2, whereas 30 preferentially inhibits CDK5. Both leads exhibited anticancer activity against acute myeloid leukemia (AML) cells via a mechanism consistent with targeting cellular CDK5. This study provides an effective strategy for discovery of CDK5 inhibitors as potential antileukemic agents.
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Affiliation(s)
| | | | - Solomon Tadesse
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Malika Kumarasiri
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Sunita K. C. Basnet
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Laychiluh B. Mekonnen
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Manjun Li
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Sarah Diab
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Matthew J. Sykes
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Hugo Albrecht
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Robert Milne
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
| | - Shudong Wang
- Centre for Drug Discovery
and Development, School of Pharmacy and Medical Sciences, Cancer Research
Institute, University of South Australia, Adelaide, SA 5001, Australia
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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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Pandey V, Ranjan N, Narne P, Babu PP. Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis. Sci Rep 2019; 9:5012. [PMID: 30899038 PMCID: PMC6428853 DOI: 10.1038/s41598-019-41380-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 02/27/2019] [Indexed: 01/01/2023] Open
Abstract
Gliomas are incurable solid tumors with extremely high relapse rate and definite mortality. As gliomas readily acquire resistance to only approved drug, temozolomide (TMZ), there is increasing need to overcome drug resistance by novel therapeutics or by repurposing the existing therapy. In the current study, we investigated antitumor efficacy of roscovitine, a Cdk inhibitor, in combination with TMZ in vitro (U87, U373, LN 18 and C6 cell lines) and in vivo (orthotopic glioma model in Wistar rats) glioma models. We observed that TMZ treatment following a pre-treatment with RSV significantly enhanced chemo-sensitivity and suppressed the growth of glioma cells by reducing Cdk-5 activity and simultaneous induction of autophagy and Caspase-3 mediated apoptosis. Additionally, reduced expression of Ki67, GFAP and markers of angiogenesis (CD31, VEGF) was observed in case of TMZ + RSV treatments. Also, presence of reactive astrocytes in peri-tumoral areas and in areas around blood vessels was completely diminished in TMZ + RSV treated brain sections. Taken together, results in the current study provide evidence that RSV in conjunction with TMZ restricts glioma growth, reduces angiogenesis and also eliminates reactive astrocytes thereby preventing the spread of glioma to adjacent healthy brain tissues and thus might be more potent therapeutic option for glioma.
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Affiliation(s)
- Vimal Pandey
- Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, AP, India
| | - Nikhil Ranjan
- Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, AP, India
| | - Parimala Narne
- Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, AP, India
| | - Phanithi Prakash Babu
- Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, AP, India.
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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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Xu C, Zhang W, Zhang X, Zhou D, Qu L, Liu J, Xiao M, Ni R, Jiang F, Ni W, Lu C. Coupling function of cyclin-dependent kinase 2 and Septin2 in the promotion of hepatocellular carcinoma. Cancer Sci 2019; 110:540-549. [PMID: 30444001 PMCID: PMC6361569 DOI: 10.1111/cas.13882] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 11/06/2018] [Accepted: 11/14/2018] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and aggressive malignant tumor with a poorly defined molecular mechanism. Cyclin-dependent kinase 2 (CDK2) and Septin2 (SEPT2) are 2 known oncogenic molecules but the mechanism of functional interactions remains unclear. Here, we interestingly found that CDK2 and SEPT2 show very similar dynamic expression during the cell cycle. Both CDK2 and SEPT2 show the highest protein levels in the G2/M phase, resulting in CDK2 interacting with SEPT2 and stabilizing SEPT2 in HCC. In a panel of 8 pairs of fresh HCC tissues and corresponding adjacent tissues, both western blot and immunohistochemistry (IHC) assays demonstrate that CDK2 expression is highly correlated with SEPT2. HCC with high expression of both CDK2 and SEPT2 are more likely to relapse. This observation is further demonstrated by a large panel of 100 HCC patients. In this large panel, high expression of both CDK2 and SEPT2 significantly correlates with tumor differentiation and microvascular invasion, which is an independent prognostic factor in HCC patients. In summary, our results reveal a cooperative function between CDK2 and SEPT2. HCC with high expression of CDK2 and SEPT2 might be more aggressive and respond poorly to current therapy.
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Affiliation(s)
- Chenzhou Xu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Wei Zhang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Xuening Zhang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Danhua Zhou
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Medical CollegeNantong UniversityNantongChina
| | - Lishuai Qu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Jinxia Liu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Mingbing Xiao
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
- Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityNantongChina
| | - Runzhou Ni
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Feng Jiang
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Wenkai Ni
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
| | - Cuihua Lu
- Department of GastroenterologyAffiliated Hospital of Nantong UniversityNantongChina
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Ardelt MA, Fröhlich T, Martini E, Müller M, Kanitz V, Atzberger C, Cantonati P, Meßner M, Posselt L, Lehr T, Wojtyniak J, Ulrich M, Arnold GJ, König L, Parazzoli D, Zahler S, Rothenfußer S, Mayr D, Gerbes A, Scita G, Vollmar AM, Pachmayr J. Inhibition of Cyclin-Dependent Kinase 5: A Strategy to Improve Sorafenib Response in Hepatocellular Carcinoma Therapy. Hepatology 2019; 69:376-393. [PMID: 30033593 PMCID: PMC6590289 DOI: 10.1002/hep.30190] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/08/2018] [Indexed: 12/29/2022]
Abstract
Therapeutic options for patients with advanced-stage hepatocellular carcinoma (HCC) are very limited. The only approved first-line treatment is the multi-tyrosine kinase inhibitor sorafenib, which shows low response rates and severe side effects. In particular, the compensatory activation of growth factor receptors leads to chemoresistance and limits the clinical impact of sorafenib. However, combination approaches to improve sorafenib have failed. Here we investigate the inhibition of cyclin-dependent kinase 5 (Cdk5) as a promising combination strategy to improve sorafenib response in HCC. Combination of sorafenib with Cdk5 inhibition (genetic knockdown by short hairpin RNA or CRISPR/Cas9 and pharmacologic inhibition) synergistically impaired HCC progression in vitro and in vivo by inhibiting both tumor cell proliferation and migration. Importantly, these effects were mediated by a mechanism for Cdk5: A liquid chromatography-tandem mass spectrometry-based proteomic approach revealed that Cdk5 inhibition interferes with intracellular trafficking, a process crucial for cellular homeostasis and growth factor receptor signaling. Cdk5 inhibition resulted in an accumulation of enlarged vesicles and respective cargos in the perinuclear region, considerably impairing the extent and quality of growth factor receptor signaling. Thereby, Cdk5 inhibition offers a comprehensive approach to globally disturb growth factor receptor signaling that is superior to specific inhibition of individual growth factor receptors. Conclusion: Cdk5 inhibition represents an effective approach to improve sorafenib response and to prevent sorafenib treatment escape in HCC. Notably, Cdk5 is an addressable target frequently overexpressed in HCC, and with Dinaciclib, a clinically tested Cdk5 inhibitor is readily available. Thus, our study provides evidence for clinically evaluating the combination of sorafenib and Dinaciclib to improve the therapeutic situation for patients with advanced-stage HCC.
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Affiliation(s)
- Maximilian A. Ardelt
- Department of Pharmacy, Pharmaceutical BiologyLMU MunichMunichGermany,Institute of PharmacyParacelsus Medical UniversitySalzburgAustria
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis, LAFUGA, Gene CentreUniversity of MunichMunichGermany
| | - Emanuele Martini
- IFOM‐FIRC Institute of Molecular OncologyDepartment of Oncology and Hemato‐OncologyUniversity of MilanMilanItalyMilanItaly
| | - Martin Müller
- Department of Pharmacy, Pharmaceutical BiologyLMU MunichMunichGermany
| | - Veronika Kanitz
- Institute of PathologyLudwig Maximilians University of MunichMunichGermany
| | - Carina Atzberger
- Department of Pharmacy, Pharmaceutical BiologyLMU MunichMunichGermany
| | - Petra Cantonati
- Institute of PharmacyParacelsus Medical UniversitySalzburgAustria
| | - Martina Meßner
- Department of Pharmacy, Pharmaceutical BiologyLMU MunichMunichGermany,Institute of PharmacyParacelsus Medical UniversitySalzburgAustria
| | - Laura Posselt
- Center of Integrated Protein Science Munich (CIPS‐M) and Division of Clinical Pharmacology, Department of Internal Medicine IVKlinikum der Universität MünchenMunichGermany
| | - Thorsten Lehr
- Clinical PharmacySaarland UniversitySaarbrückenGermany
| | | | - Melanie Ulrich
- Department of Pharmacy, Pharmaceutical BiologyLMU MunichMunichGermany
| | - Georg J. Arnold
- Laboratory for Functional Genome Analysis, LAFUGA, Gene CentreUniversity of MunichMunichGermany
| | - Lars König
- Center of Integrated Protein Science Munich (CIPS‐M) and Division of Clinical Pharmacology, Department of Internal Medicine IVKlinikum der Universität MünchenMunichGermany
| | - Dario Parazzoli
- IFOM‐FIRC Institute of Molecular OncologyDepartment of Oncology and Hemato‐OncologyUniversity of MilanMilanItalyMilanItaly
| | - Stefan Zahler
- Department of Pharmacy, Pharmaceutical BiologyLMU MunichMunichGermany
| | - Simon Rothenfußer
- Center of Integrated Protein Science Munich (CIPS‐M) and Division of Clinical Pharmacology, Department of Internal Medicine IVKlinikum der Universität MünchenMunichGermany
| | - Doris Mayr
- Institute of PathologyLudwig Maximilians University of MunichMunichGermany
| | - Alexander Gerbes
- Department of Medicine 2, Liver Center MunichUniversity Hospital, LMU MunichMunichGermany
| | - Giorgio Scita
- IFOM‐FIRC Institute of Molecular OncologyDepartment of Oncology and Hemato‐OncologyUniversity of MilanMilanItalyMilanItaly
| | | | - Johanna Pachmayr
- Department of Pharmacy, Pharmaceutical BiologyLMU MunichMunichGermany,Institute of PharmacyParacelsus Medical UniversitySalzburgAustria
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Lin JX, Xie XS, Weng XF, Zheng CH, Xie JW, Wang JB, Lu J, Chen QY, Cao LL, Lin M, Tu RH, Huang CM, Li P. The prognostic value of Cyclin-Dependent Kinase 5 and Protein Phosphatase 2A in Gastric Cancer. J Cancer 2018; 9:4404-4412. [PMID: 30519346 PMCID: PMC6277666 DOI: 10.7150/jca.27015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 08/02/2018] [Indexed: 11/16/2022] Open
Abstract
Purpose To discuss the relationship between the clinicopathological data, long-term survival of gastric cancer patients and different expression levels of Cyclin-Dependent Kinase 5 (CDK5) and Protein Phosphatase 2A (PP2A). Method The expression levels of CDK5 and PP2A were detected by immunohistochemistry in specimens from 124 patients with primary gastric cancer. The correlation among the expression of CDK5 and PP2A, clinicopathological factors and prognosis was investigated. Result The expression level of CDK5 was correlated with the TNM stage (p=0.030) and N stage (p=0.001), while the expression level of PP2A was correlated with the TNM stage and N stage (p=0.001 and p=0.004) as well as the degree of differentiation (p=0.046). The expression of CDK5 was positively correlated with the expression of PP2A in gastric cancer. Co-expression of CDK5 and PP2A is an independent prognostic factor that affected overall survival, and provided more accurate prognostic value for the overall survival of gastric cancer patients. Conclusion The expression of CDK5 and PP2A is positively correlated in gastric cancer. Co-expression of CDK5 and PP2A was an independent prognostic factor in patients with gastric cancer.
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Affiliation(s)
- Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xin-Sheng Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xiong-Feng Weng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Ru-Hong Tu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian Province, China
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Qin Y, Kang A, Zhou G, Wang H, Wei W, Cao Y, Chen Y, Wang J, Shi Y, Tang Y, Jiang J. Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan: In vitro
and in vivo
insights from quantitative ultra-performance liquid chromatography-mass spectrometry analysis. Biomed Chromatogr 2018; 32:e4320. [DOI: 10.1002/bmc.4320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/04/2018] [Accepted: 06/09/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Yifeng Qin
- College of Pharmacy and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization; Shaanxi University of Chinese Medicine; Xi'an Shaanxi Province China
- School of Traditional Chinese Pharmacy; China Pharmaceutical University; Nanjing Jiangsu Province China
| | - An Kang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae; Nanjing University of Chinese Medicine; Nanjing Jiangsu Province China
| | - Guisheng Zhou
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae; Nanjing University of Chinese Medicine; Nanjing Jiangsu Province China
| | - Huan Wang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae; Nanjing University of Chinese Medicine; Nanjing Jiangsu Province China
| | - Wei Wei
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae; Nanjing University of Chinese Medicine; Nanjing Jiangsu Province China
| | - Yujie Cao
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae; Nanjing University of Chinese Medicine; Nanjing Jiangsu Province China
| | - Yanyan Chen
- College of Pharmacy and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization; Shaanxi University of Chinese Medicine; Xi'an Shaanxi Province China
| | - Jing Wang
- College of Pharmacy and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization; Shaanxi University of Chinese Medicine; Xi'an Shaanxi Province China
| | - Yajun Shi
- College of Pharmacy and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization; Shaanxi University of Chinese Medicine; Xi'an Shaanxi Province China
| | - Yuping Tang
- College of Pharmacy and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization; Shaanxi University of Chinese Medicine; Xi'an Shaanxi Province China
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae; Nanjing University of Chinese Medicine; Nanjing Jiangsu Province China
| | - Jianqin Jiang
- School of Traditional Chinese Pharmacy; China Pharmaceutical University; Nanjing Jiangsu Province China
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Abstract
Cdk5 is an atypical cyclin-dependent kinase that is well characterized for its role in the central nervous system rather than in the cell cycle. However Cdk5 has been recently implicated in the development and progression of a variety of cancers including breast, lung, colon, pancreatic, melanoma, thyroid and brain tumors. This broad pro-tumorigenic role makes Cdk5 a promising drug target for the development of new cancer therapies. Here we review the contribution of Cdk5 to molecular mechanisms that confer upon tumors the ability to grow, proliferate and disseminate to secondary organs, as well as resistance to chemotherapies. We subsequently discuss existing and new strategies for targeting Cdk5 and its downstream mechanisms as anti-cancer treatments.
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Robb CM, Kour S, Contreras JI, Agarwal E, Barger CJ, Rana S, Sonawane Y, Neilsen BK, Taylor M, Kizhake S, Thakare RN, Chowdhury S, Wang J, Black JD, Hollingsworth MA, Brattain MG, Natarajan A. Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy. Oncotarget 2017; 9:5216-5232. [PMID: 29435174 PMCID: PMC5797045 DOI: 10.18632/oncotarget.23749] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/10/2017] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 - now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ∼3.5-fold and ∼65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average >2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy.
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Affiliation(s)
- Caroline M Robb
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Smit Kour
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Jacob I Contreras
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Ekta Agarwal
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Carter J Barger
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Sandeep Rana
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Yogesh Sonawane
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Beth K Neilsen
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Margaret Taylor
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Smitha Kizhake
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Rhishikesh N Thakare
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Sanjib Chowdhury
- Section of Gastroenterology, Department of Medicine, Boston University Medical Center, Boston, Massachusetts 02118, USA
| | - Jing Wang
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Jennifer D Black
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Michael G Brattain
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Amarnath Natarajan
- Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.,Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
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