Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73

doi:10.18632/oncotarget.2296

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73
	Lam, Frankie 4,5; Abbas, Abdullahi Y.1,6; Shao, Hao 1,6; Teo, Theodosia 4,5; Adams, Julian 4,5; Li, Peng 4,5; Bradshaw, Tracey D.1,6; Fischer, Peter M.1,6; Walsby, Elisabeth 3; Pepper, Chris 3
刊名	ONCOTARGET
	2014-09-15
卷号	5 期号:17 页码:7691-7704
关键词	CDK9 shRNA Mnks eIF4E kinase inhibitors PI3K/Akt/mTOR Ras/Raf/MAPK Flavopiridol CGP57380 apoptosis transcription translation drug development
ISSN号	1949-2553
DOI	10.18632/oncotarget.2296
文献子类	Article
英文摘要	Dysregulation of cellular transcription and translation is a fundamental hallmark of cancer. As CDK9 and Mnks play pivotal roles in the regulation of RNA transcription and protein synthesis, respectively, they are important targets for drug development. We herein report the cellular mechanism of a novel CDK9 inhibitor CDKI-73 in an ovarian cancer cell line (A2780). We also used shRNA-mediated CDK9 knockdown to investigate the importance of CDK9 in the maintenance of A2780 cells. This study revealed that CDKI-73 rapidly inhibited cellular CDK9 kinase activity and down-regulated the RNAPII phosphorylation. This subsequently caused a decrease in the eIF4E phosphorylation by blocking Mnk1 kinase activity. Consistently, CDK9 shRNA was also found to down-regulate the Mnk1 expression. Both CDKI-73 and CDK9 shRNA decreased anti-apoptotic proteins Mcl-1 and Bcl-2 and induced apoptosis. The study confirmed that CDK9 is required for cell survival and that ovarian cancer may be susceptible to CDK9 inhibition strategy. The data also implied a role of CDK9 in eIF4E-mediated translational control, suggesting that CDK9 may have important implication in the Mnk-eIF4E axis, the key determinants of PI3K/Akt/mTOR- and Ras/Raf/MAPK-mediated tumorigenic activity. As such, CDK9 inhibitor drug candidate CDKI-73 should have a major impact on these pathways in human cancers.
资助项目	Cancer Research UK[17648]
WOS关键词	DEPENDENT KINASE INHIBITOR ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; X-RAY CRYSTALLOGRAPHY ; INITIATION-FACTOR 4E ; IN-VITRO ; CDK INHIBITORS ; R-ROSCOVITINE ; INTERACTING KINASES ; ANTITUMOR-ACTIVITY ; CLINICAL-TRIALS
WOS研究方向	Oncology ; Cell Biology
语种	英语
出版者	IMPACT JOURNALS LLC
WOS记录号	WOS:000348029800038
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276901]
专题	药理学第一研究室
通讯作者	Wang, Shudong
作者单位	1.Univ Nottingham, Ctr Biomol Sci, Nottingham NG7 2RD, England; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China 3.Cardiff Univ, Sch Med, Inst Canc & Genet, Cardiff CLL Res Grp, Cardiff CF10 3AX, S Glam, Wales; 4.Univ S Australia, Ctr Drug Discovery & Dev, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia; 5.Univ S Australia, Sch Pharm & Med Sci, Adelaide, SA 5001, Australia; 6.Univ Nottingham, Sch Pharm, Nottingham NG7 2RD, England;
推荐引用方式 GB/T 7714	Lam, Frankie,Abbas, Abdullahi Y.,Shao, Hao,et al. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73[J]. ONCOTARGET,2014,5(17):7691-7704.
APA	Lam, Frankie.,Abbas, Abdullahi Y..,Shao, Hao.,Teo, Theodosia.,Adams, Julian.,...&Wang, Shudong.(2014).Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73.ONCOTARGET,5(17),7691-7704.
MLA	Lam, Frankie,et al."Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73".ONCOTARGET 5.17(2014):7691-7704.