Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations

Abstract

Mutant p53 proteins (mutant p53s) have oncogenic gain-of-function properties correlated with tumor grade, castration resistance, and prostate cancer (PCa) tumor recurrence. Docetaxel is a standard first-line treatment for metastatic castration-resistant PCa (mCRPC) after the failure of hormone therapy. However, most mCRPC patients who receive docetaxel experience only transient benefits and rapidly develop incurable drug resistance, which is closely correlated with the p53 mutation status. Mutant p53s were recently reported to regulate the metabolic pathways via sterol regulatory element-binding proteins (SREBPs). Therefore, targeting the SREBP metabolic pathways with docetaxel as a combination therapy may offer a potential strategy to improve anti-tumor efficacy and delay cellular drug resistance in mCRPC harboring mutant p53s. Our previous data showed that fatostatin, a new SREBP inhibitor, inhibited cell proliferation and induced apoptosis in androgen receptor (AR)-positive PCa cell lines and xenograft mouse models. In this study, we demonstrated that mutant p53s activate the SREBP-mediated metabolic pathways in metastatic AR-negative PCa cells carrying mutant p53s. By blocking the SREBP pathways, fatostatin inhibited cell growth and induced apoptosis in metastatic AR-negative PCa cells harboring mutant p53s. Furthermore, the combination of fatostatin and docetaxel resulted in greater proliferation inhibition and apoptosis induction compared with single agent treatment in PCa cells in vitro and in vivo, especially those with mutant p53s. These data suggest for the first time that fatostatin alone or in combination with docetaxel could be exploited as a novel and promising therapy for metastatic PCa harboring p53 mutations.