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
Chung-Sheng Shi,
Kuan-Lin Kuo,
Mei-Sin Chen,
Po-Ming Chow,
Shing-Hwa Liu,
Yu-Wei Chang,
Wei-Chou Lin,
Shih-Ming Liao,
Chen-Hsun Hsu,
Fu-Shun Hsu,
Hong-Chiang Chang,
Kuo-How Huang
Affiliations
Chung-Sheng Shi
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
Kuan-Lin Kuo
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Mei-Sin Chen
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
Po-Ming Chow
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Shing-Hwa Liu
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Yu-Wei Chang
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Wei-Chou Lin
Department of Pathology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Shih-Ming Liao
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Chen-Hsun Hsu
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Fu-Shun Hsu
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 106, Taiwan
Hong-Chiang Chang
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
Kuo-How Huang
Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan
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.
