https://scholars.lib.ntu.edu.tw/handle/123456789/541921
標題: | 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 | 作者: | Shi C.-S. Kuo K.-L. Chen M.-S. PO-MING CHOW Liu S.-H. Chang Y.-W. WEI-CHOU LIN Liao S.-M. Hsu C.-H. Hsu F.-S. HONG-CHIANG CHANG KUO-HOW HUANG |
公開日期: | 2019 | 出版社: | NLM (Medline) | 卷: | 8 | 期: | 11 | 來源出版物: | Cells | 摘要: | 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. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081733327&doi=10.3390%2fcells8111469&partnerID=40&md5=6b62853914c4a18109c26b4523f9d17d https://scholars.lib.ntu.edu.tw/handle/123456789/541921 |
ISSN: | 2073-4409 | DOI: | 10.3390/cells8111469 | SDG/關鍵字: | cyclin dependent kinase; cyclin-dependent kinase-activating kinase; protein kinase inhibitor; animal; cell motion; cell proliferation; disease model; drug effect; drug screening; human; kidney tumor; metabolism; mouse; neovascularization (pathology); pathology; renal cell carcinoma; tumor cell line; umbilical vein endothelial cell; Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinases; Disease Models, Animal; Human Umbilical Vein Endothelial Cells; Humans; Kidney Neoplasms; Mice; Neovascularization, Pathologic; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays |
顯示於: | 醫學系 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。