IDO1 Modulates the Sensitivity of Epithelial Ovarian Cancer Cells to Cisplatin through ROS/p53-Dependent Apoptosis

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase that may play a part in chemoresistance in ovarian cancer. However, its role in cisplatin (DDP) resistance is unclear. Here, the expression level of IDO1 in tumors in platinum-resistant (n = 22) and -sensitive (n = 46) ovarian cancer patients was determined, and then how IDO1 modulated DDP resistance was explored in vitro and in vivo. The IDO1 expression level in platinum-resistant patients was higher than that in -sensitive patients, and a higher IDO1 level was correlated with poor prognosis in type II cancer patients. Up-regulating IDO1 decreased DDP-induced apoptosis in SKOV3 cells via inhibiting the ROS/p53 cell-death pathway, thereby attenuating cytotoxicity of DDP. Silencing IDO1 enhanced p53-dependent apoptosis by increasing ROS accumulation, thereby enhancing DDP against SKOV3 cells. Down-knocking IDO1 augmented the action of DDP in vivo. These data demonstrated that silencing IDO1 enhanced the efficacy of DDP by intensifying p53-dependent apoptosis, and that targeting IDO1 can be a strategy to modulate DDP-based chemotherapy for epithelial ovarian cancer.

Keywords

• cisplatin
• indoleamine 2,3-dioxygenase 1
• ovarian cancer
• p53
• reactive oxygen species