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Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73
journal contribution
posted on 2023-06-09, 11:29 authored by Frankie Lam, Abdullahi Y Abbas, Hao Shao, Theodosia Teo, Julian Adams, Peng Li, Tracey D Bradshaw, Peter M Fischer, Elisabeth Walsby, Christopher PepperChristopher Pepper, Yi Chen, Jian Ding, Shudong WangDysregulation 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.
History
Publication status
- Published
File Version
- Published version
Journal
OncotargetISSN
1949-2553Publisher
Impact JournalsExternal DOI
Issue
17Volume
5Page range
7691-7704Department affiliated with
- BSMS Publications
Research groups affiliated with
- Haematology Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-01-10First Open Access (FOA) Date
2018-01-10First Compliant Deposit (FCD) Date
2018-01-10Usage metrics
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