Reference | 1. Oncotarget. 2014 Sep 15;5(17):7691-704.
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Targeting RNA transcription and translation in ovarian cancer cells with
pharmacological inhibitor CDKI-73.
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Lam F(1), Abbas AY(2), Shao H(2), Teo T(1), Adams J(1), Li P(1), Bradshaw TD(2),
Fischer PM(2), Walsby E(3), Pepper C(3), Chen Y(4), Ding J(4), Wang S(5).
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Author information: <br>
(1)Centre for Drug Discovery and Development, Sansom Institute for Health
Research and School of Pharmacy and Medical Sciences, University of South
Australia, Adelaide, South Australia, Australia.
(2)School of Pharmacy and Centre for Biomolecular Sciences, University of
Nottingham, University Park, Nottingham, United Kingdom.
(3)Cardiff CLL Research Group, Institute of Cancer and Genetics, School of
Medicine, Cardiff University, Health Park, Cardiff, United Kingdom.
(4)Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai,
People’s Republic of China.
(5)Centre for Drug Discovery and Development, Sansom Institute for Health
Research and School of Pharmacy and Medical Sciences, University of South
Australia, Adelaide, South Australia, Australia. School of Pharmacy and Centre
for Biomolecular Sciences, University of Nottingham, University Park, Nottingham,
United Kingdom.
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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.
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