title: Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73.
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 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.
authors.affiliation: 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.
authors.forename: Frankie
authors.initials: F
authors.lastname: Lam
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
authors.forename: Abdullahi Y
authors.initials: AY
authors.lastname: Abbas
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
authors.forename: Hao
authors.initials: H
authors.lastname: Shao
authors.affiliation: 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.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Teo
authors.affiliation: 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.
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.affiliation: 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.affiliation: Cardiff CLL Research Group, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Health Park, Cardiff, United Kingdom.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Walsby
authors.affiliation: Cardiff CLL Research Group, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Health Park, Cardiff, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology*; D014176:Protein Biosynthesis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D012313:RNA; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D042863:Cyclin-Dependent Kinase 9; D011743:Pyrimidines; D012313:RNA; D013449:Sulfonamides; C000599930:3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzenesulfonamide; D000096926:Benzenesulfonamides; C467969:CDK9 protein, human