The tumor suppressor p53 prevents cancer development via regulating cell cycle arrest, cell death, or repair processes. Over 50% of human cancers harbor mutant p53. Mutations in p53 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 chemotherapeutic resistance. Thus, targeting mutant p53 to restore wild-type p53 pathway signaling is an attractive strategy for cancer therapy. We previously reported a novel small molecular compound, NCI-8, which not only restores wild-type p53 signaling, but also depletes mutant p53 protein (Zhang S, Zhou L, Hong B, et al. Cancer Res 2013;73(8 Suppl):Abstract 2171). In this study, we further elucidate the mechanism of the small molecular compound NCI-8-mediated degradation of mutant p53 protein. We found that the small molecule NCI-8 induces mutant p53 protein degradation via the MDM2-ubiquitin-proteasome pathway. NCI-8 exposure leads to phosphorylation of p53 at Thr55. Dephosphorylation of p53 at Thr55 rescues mutant p53 protein from degradation in cells treated with Apigenin, suggesting that phosphorylation at Thr55 is required for mutant p53 protein degradation induced by NCI-8. Hsp90 and hsp70 are two molecular chaperones that stabilize mutant p53 protein by affecting the MDM2 mediated turnover of mutant p53, therefore, we investigated the effect of NCI-8 on the MDM2-hsp chaperone axis. We found that less HSP90 but more MDM2 were bound to mutant p53 in cells treated with NCI-8, suggesting that NCI-8 induces mutant p53 protein degradation through disturbing the MDM2-hsp chaperone axis. Correlated to the degradation of mutant p53 protein, the p73 pathway was activated in response to NCI-8 treatment specifically in mutant p53-expressing colorectal cancer cells. Our results provide a possible mechanism of NCI-8-mediated p73-dependent restoration of the p53 pathway via mutant p53 protein degradation.

Citation Format: Shengliang Zhang, Lanlan Zhou, Christina Leah B. Kline, David T. Dicker, Wafik S. El-Deiry. Small molecule compound NCI-8 induces mutant p53 degradation via inhibition of the MDM2-Hsp90 axis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1802. doi:10.1158/1538-7445.AM2014-1802