Curcumin re-sensitizes multidrug resistant (MDR) breast cancer to cisplatin through inducing autophagy by decreasing CCAT1 expression

Abstract

Multidrug resistance (MDR) is a major obstacle to the chemotherapeutic treatment of breast cancer. The aim of this study is to investigate the mechanisms of curcumin induced increased chemosensitivity in MDR breast cancer cells. The results of MTT and western blot showed that curcumin could sensitize MCF-7 and MCF-7/DDP cells to cisplatin and activate MCF-7/DDP cell autophagy. The levels of CCAT1, p-PI3K, p-AKT and p-mTOR detected by RT-PCR and western blot in MCF-7/DDP cells were higher than in MCF-7 cells, and curcumin downregulated their expression in a dose-dependent manner. Moreover, we found that downregulation of CCAT1 could re-sensitize MCF-7/DDP cells to cisplatin, inactivate the PI3K/AKT/mTOR pathway and activate cell autophagy, while overexpression of it have the opposite effect in MCF-7 cells. Inactivation of autophagy by 3-MA could reverse CCAT1 knockdown-induced increased chemosensitivity and inactivation of the PI3K/AKT/mTOR pathway in MCF-7/DDP cells. PLEN-CCAT1 could reverse curcumin-increased chemosensitivity and autophagy activation, however, inactivation of the PI3K/AKT/mTOR pathway by LY294002 could reverse once more pLEN-CCAT1-decreased chemosensitivity and inactivation of autophagy. Finally, the xenotransplant nude mouse model was used to study the effect of CCAT1 on curcumin-induced autophagy in vivo, and the results showed that curcumin inhibited tumor volume growth, downregulated CCAT1 expression and induced autophagy in vivo. Curcumin decreased CCAT1 and inactivated the PI3K/Akt/mTOR pathway which could both activate autophagy, sensitizing MDR breast cancer cells to cisplatin.