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,Hong-Chiang Chang,Kuan-Lin Kuo,Chen-Hsun Hsu,Kuo-How Huang,Wei-Chou Lin,Po-Ming Chow,Mei-Sin Chen,Shih-Ming Liao,Yu-Wei Chang,Fu-Shun Hsu,Shing-Hwa Liu

doi:10.3390/cells8111469

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.

Highlights

IntroductionVascular endothelial growth factor (VEGF)-mediated vascular endothelial growth factor (VEGF) receptor 1 and 2 (VEGFR1/2) signaling plays critical roles in the angiogenic activity of the endothelium [2]
Dysregulated angiogenesis plays a crucial role in tumor growth and metastasis [1]
We evaluated the role of CDK7 in regulating the angiogenic activity of human umbilical vascular endothelial cells (HUVECs), as well as the antiangiogenic and antitumor effects of

Summary

Introduction

Vascular endothelial growth factor (VEGF)-mediated VEGF receptor 1 and 2 (VEGFR1/2) signaling plays critical roles in the angiogenic activity of the endothelium [2]. CDKs are important in regulating cell cycle progression and gene transcription, and CDK deregulation has been observed in human malignancies. The functions of CDK7–13 are linked to transcription, and CDK1, 2, 4, and 6 are associated with cell cycle regulation. CDK7 plays a dual role of regulating both cell cycle and transcription. Nuclear CDK7 associates with the kinase core of the RNAPII transcription factor complex by phosphorylating the CTD of RNAPII, after which gene transcription can be initiated [12,13]. CTD phosphorylation of CDK7 is critical for modulating cell proliferation, cell cycle progression, and cell apoptosis.

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