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

Lam, Frankie, Abbas, Abdullahi Y, Shao, Hao, Teo, Theodosia, Adams, Julian, Li, Peng, Bradshaw, Tracey D, Fischer, Peter M, Walsby, Elisabeth, Pepper, Chris, Chen, Yi, Ding, Jian and Wang, Shudong (2014) Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget, 5 (17). pp. 7691-7704. ISSN 1949-2553

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Abstract

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 downregulated
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 eIF4Emediated
translational control, suggesting that CDK9 may have important implication
in the Mnk-eIF4E axis, the key determinants of PI3K/Akt/mTOR- and Ras/Raf/MAPKmediated
tumorigenic activity. As such, CDK9 inhibitor drug candidate CDKI-73 should
have a major impact on these pathways in human cancers.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
Depositing User: Gemma Hamilton
Date Deposited: 10 Jan 2018 10:31
Last Modified: 10 Jan 2018 10:31
URI: http://sro.sussex.ac.uk/id/eprint/72708

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