Vitamin D3 sensitizes resistant human bladder cancer cells to cisplatin by regulating Sirtuin 1 gene expression.

Abstract

Cisplatin is a standard chemotherapeutic agent for advanced bladder cancer, but its efficacy is limited due to drug resistance. Vitamin D3 may reverse cancer multidrug resistance, but the potential molecular mechanisms are still only partially known. The purpose of this study was to explore the mechanism by which vitamin D3 reverses cisplatin resistance in bladder cancer to improve therapeutic efficacy and ameliorate the prognosis of cisplatin-resistant bladder cancer. The levels of vitamin D3 and sirtuin 1 protein were detected in cisplatin-resistant bladder cancer patients and cisplatin-sensitive patients. The cisplatin-resistant bladder cancer cell lines T24/DDP and UMUC3R were used as cell experimental models, and the migration, apoptosis, mitochondrial reactive oxygen species accumulation and autophagy of cells were assessed in the present study. Vitamin D3 levels were decreased, and sirtuin 1 protein levels were increased in cisplatin-resistant bladder cancer patients compared with cisplatin-sensitive bladder cancer patients. Vitamin D3 treatment markedly repressed sirtuin 1 expression, and overexpression of the sirtuin 1 gene led to mitochondrial reactive oxygen species generation, promoted the initiation of autophagosome formation and enhanced autophagic flux. Cisplatin treatment in the presence of vitamin D3 inhibited cell invasion and migration and induced apoptosis and enhancing the sirtuin 1 gene abolished the effect of vitamin D3 by regulating mitochondrial reactive oxygen species accumulation and autophagosome formation. These data support a mechanism wherein the sirtuin 1 gene plays a crucial role in vitamin D3 reversing cisplatin resistance in bladder cancer and may provide useful preventive and therapeutic applications in the future.