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*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

8 Scopus citations

Abstract

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.

Original languageEnglish
Article number1469
JournalCells
Volume8
Issue number11
DOIs
StatePublished - 11 2019

Bibliographical note

Publisher Copyright:
© MDPI AG. All rights reserved.

Keywords

  • Angiogenesis
  • Cyclin-dependent kinase 7
  • Endothelial cell
  • Renal cell carcinoma
  • THZ1

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this