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Zhang S , Zhou L , Hong B , van den Heuvel AP , Prabhu VV , Warfel NA , Kline CL , Dicker DT , Kopelovich L , El-Deiry WS
Small molecule NSC59984 restores p53 pathway signaling and anti-tumor effects against colorectal cancer via p73 activation and degradation of mutant p53
Cancer Res. 2015 Aug 20;75(18) :3842-52
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Abstract
The tumor suppressor p53 prevents cancer development via initiating cell cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor suppressor function, but also endow mutant p53 with a gain-of-function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity towards normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73- notdependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anti-cancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anti-cancer therapy that acts by targeting GOF mutant p53 and stimulates p73 to restore the p53 pathway signaling.
Notes
Zhang, Shengliang Zhou, Lanlan Hong, Bo van den Heuvel, A Pieter J Prabhu, Varun V Warfel, Noel A Kline, Christina Leah B Dicker, David T Kopelovich, Levy El-Deiry, Wafik S R01 CA176289/CA/NCI NIH HHS/United States Cancer Res. 2015 Aug 20. pii: canres.1079.2013.