期刊
CELLULAR SIGNALLING
卷 67, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2019.109508
关键词
iASPP; p53 reactivation; CDK9 inhibitor; Concurrent inhibition; MDM2
类别
资金
- National Key RAMP
- D Program of China [2017YFA0506200]
- National Natural Science Foundation of China for Excellent Young Scholars [81622002, 81861130368, 81900157]
- Academy of Medical Sciences-Newton Advanced Fellowship
- Clinical Research Program of Ruijin Hospital [2018CR006]
- Shanghai Medical and Health Excellent Discipline Leader Development Plan [2018BR36]
- Shanghai Youth Talent Development Program [2017275]
- Shanghai Collaborative Innovation Center for Translational Medicine [TM201902]
Loss of p53's tumor-suppressive function, either via TP53 mutation or hyperactive p53 inhibitory proteins, is one of the most frequent events in the development of human cancer. Here, we describe a strategy of pharmacologically inhibiting iASPP, a negative regulator of p53, to restore wild-type p53's tumor-suppressive function. iASPP knockdown in the colon cancer cell line HCT116 efficiently promoted p53's transcriptional activity and induced p53-dependent cell death, suggesting a key role for iASPP in silencing p53 in this cell line. Screening of a preclinical and clinical drug library using isogenic HCT116 cell models revealed that cyclin-dependent kinase 9 (CDK9) inhibitors preferentially inhibit p53(+/+), rather than p53(-/-), cells. Mechanistically, CDK9 inhibitors downregulated iASPP at the transcriptional level. This downregulation was dose- and time-dependent. CDK9 inhibitors further showed synergistic effects in killing p53(+/+) HCT116 cells when combined with the MDM2 inhibitor Nutlin-3. In a large TCGA pan-cancer cohort, iASPP overexpression predicted poor overall survival (OS) in wild-type p53 patients, with worse OS observed when MDM2 was simultaneously overexpressed. Our study identifies CDK9 inhibitors as p53-reactivating agents, and proposes a strategy to treat cancer by efficiently reactivating p53 via the concurrent inhibition of iASPP and MDM2.
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