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Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study

Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human can...

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Autores principales: Shi, Chung-Sheng, Kuo, Kuan-Lin, Chen, Mei-Sin, Chow, Po-Ming, Liu, Shing-Hwa, Chang, Yu-Wei, Lin, Wei-Chou, Liao, Shih-Ming, Hsu, Chen-Hsun, Hsu, Fu-Shun, Chang, Hong-Chiang, Huang, Kuo-How
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912535/
https://www.ncbi.nlm.nih.gov/pubmed/31752390
http://dx.doi.org/10.3390/cells8111469
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author Shi, Chung-Sheng
Kuo, Kuan-Lin
Chen, Mei-Sin
Chow, Po-Ming
Liu, Shing-Hwa
Chang, Yu-Wei
Lin, Wei-Chou
Liao, Shih-Ming
Hsu, Chen-Hsun
Hsu, Fu-Shun
Chang, Hong-Chiang
Huang, Kuo-How
author_facet Shi, Chung-Sheng
Kuo, Kuan-Lin
Chen, Mei-Sin
Chow, Po-Ming
Liu, Shing-Hwa
Chang, Yu-Wei
Lin, Wei-Chou
Liao, Shih-Ming
Hsu, Chen-Hsun
Hsu, Fu-Shun
Chang, Hong-Chiang
Huang, Kuo-How
author_sort Shi, Chung-Sheng
collection PubMed
description Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. In this study, we investigated the role and therapeutic potential of CDK7 in regulating the angiogenic activity of endothelial cells and human renal cell carcinoma (RCC). Our results revealed that vascular endothelial growth factor (VEGF), a critical activator of angiogenesis, upregulated the expression of CDK7 and RNAPII, and the phosphorylation of RNAPII at serine 5 and 7 in human umbilical vein endothelial cells (HUVECs), indicating the transcriptional activity of CDK7 may be involved in VEGF-activated angiogenic activity of endothelium. Furthermore, through suppressing CDK7 activity, THZ1 suppressed VEGF-activated proliferation and migration, as well as enhanced apoptosis of HUVECs. Moreover, THZ1 inhibited VEGF-activated capillary tube formation and CDK7 knockdown consistently diminished tube formation in HUVECs. Additionally, THZ1 reduced VEGF expression in human RCC cells (786-O and Caki-2), and THZ1 treatment inhibited tumor growth, vascularity, and angiogenic marker (CD31) expression in RCC xenografts. Our results demonstrated that CDK7-mediated transcription was involved in the angiogenic activity of endothelium and human RCC. THZ1 suppressed VEGF-mediated VEGFR2 downstream activation of angiogenesis, providing a new perspective for antitumor therapy in RCC patients.
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spelling pubmed-69125352020-01-02 Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study Shi, Chung-Sheng Kuo, Kuan-Lin Chen, Mei-Sin Chow, Po-Ming Liu, Shing-Hwa Chang, Yu-Wei Lin, Wei-Chou Liao, Shih-Ming Hsu, Chen-Hsun Hsu, Fu-Shun Chang, Hong-Chiang Huang, Kuo-How Cells Article Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. In this study, we investigated the role and therapeutic potential of CDK7 in regulating the angiogenic activity of endothelial cells and human renal cell carcinoma (RCC). Our results revealed that vascular endothelial growth factor (VEGF), a critical activator of angiogenesis, upregulated the expression of CDK7 and RNAPII, and the phosphorylation of RNAPII at serine 5 and 7 in human umbilical vein endothelial cells (HUVECs), indicating the transcriptional activity of CDK7 may be involved in VEGF-activated angiogenic activity of endothelium. Furthermore, through suppressing CDK7 activity, THZ1 suppressed VEGF-activated proliferation and migration, as well as enhanced apoptosis of HUVECs. Moreover, THZ1 inhibited VEGF-activated capillary tube formation and CDK7 knockdown consistently diminished tube formation in HUVECs. Additionally, THZ1 reduced VEGF expression in human RCC cells (786-O and Caki-2), and THZ1 treatment inhibited tumor growth, vascularity, and angiogenic marker (CD31) expression in RCC xenografts. Our results demonstrated that CDK7-mediated transcription was involved in the angiogenic activity of endothelium and human RCC. THZ1 suppressed VEGF-mediated VEGFR2 downstream activation of angiogenesis, providing a new perspective for antitumor therapy in RCC patients. MDPI 2019-11-19 /pmc/articles/PMC6912535/ /pubmed/31752390 http://dx.doi.org/10.3390/cells8111469 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shi, Chung-Sheng
Kuo, Kuan-Lin
Chen, Mei-Sin
Chow, Po-Ming
Liu, Shing-Hwa
Chang, Yu-Wei
Lin, Wei-Chou
Liao, Shih-Ming
Hsu, Chen-Hsun
Hsu, Fu-Shun
Chang, Hong-Chiang
Huang, Kuo-How
Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study
title Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study
title_full Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study
title_fullStr Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study
title_full_unstemmed Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study
title_short Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study
title_sort suppression of angiogenesis by targeting cyclin-dependent kinase 7 in human umbilical vein endothelial cells and renal cell carcinoma: an in vitro and in vivo study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912535/
https://www.ncbi.nlm.nih.gov/pubmed/31752390
http://dx.doi.org/10.3390/cells8111469
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