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

Autor:	Yu-Wei Chang, Hong-Chiang Chang, Fu-Shun Hsu, Chen-Hsun Hsu, Shing-Hwa Liu, Po-Ming Chow, Kuo-How Huang, Wei-Chou Lin, Chung-Sheng Shi, Shih-Ming Liao, Mei-Sin Chen, Kuan-Lin Kuo
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	CD31 renal cell carcinoma Endothelium Angiogenesis Article chemistry.chemical_compound Mice angiogenesis Cyclin-dependent kinase Cell Movement Cell Line Tumor medicine Human Umbilical Vein Endothelial Cells Animals Humans Carcinoma Renal Cell Protein Kinase Inhibitors lcsh:QH301-705.5 Cell Proliferation Tube formation cyclin-dependent kinase 7 biology Neovascularization Pathologic Chemistry General Medicine Xenograft Model Antitumor Assays Cyclin-Dependent Kinases Kidney Neoplasms Vascular endothelial growth factor Endothelial stem cell Disease Models Animal medicine.anatomical_structure lcsh:Biology (General) Cancer cell Cancer research biology.protein endothelial cell thz1 Cyclin-Dependent Kinase-Activating Kinase
Zdroj:	Cells, Vol 8, Iss 11, p 1469 (2019) Cells Volume 8 Issue 11
ISSN:	2073-4409
Popis:	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.
Databáze:	OpenAIRE
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