Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling
Lan Yin, Yuhan Yang, Wanglong Zhu, Yu Xian, Zhengyu Han, Houyi Huang, Liaotian Peng, Kun Zhang, Ye Zhao
Abstract
Ovarian cancer is the most lethal gynaecologic tumor, with which multi-drug resistance as the major therapeutic hindrance. Heat shock protein 90 (Hsp90) has been involved in cancer malignant behaviors. However, its role and mechanism in multi-drug resistance of ovarian cancer remains poorly understood. Our results demonstrated that Hsp90 was overexpressed in multi-drug resistant ovarian cancer cells. Hsp90 downregulation by shHsp90 or inhibitor BIIB021 increased the sensitivity of multi-drug resistant ovarian cancer cells to paclitaxel and cisplatin, and augmented the drugs-induced apoptosis. Hsp90 positively regulated the expressions of multi-drug resistance protein 1 (P-gp/MDR1), breast cancer resistance protein (BCRP), Survivin and Bcl-2 expressions closely associated with multi-drug resistance. Moreover, overexpression of Hsp90 promoted β-catenin accumulation, while Hsp90 downregulation decreased the accumulation, nuclear translocation and transcriptional activity of β-catenin. We also identified that β-catenin was responsible for Hsp90-mediated expressions of P-gp, BCRP, Survivin, and Bcl-2. Furthermore, Hsp90 enhanced the AKT/GSK3β signaling, and AKT signaling played a critical role in Hsp90-induced accumulation and transcriptional activity of β-catenin, as well as multi-drug resistance to paclitaxel and cisplatin. In conclusion, Hsp90 enhanced the AKT/GSK3β/β-catenin signaling to induce multi-drug resistance of ovarian cancer. Suppressing Hsp90 chemosensitized multi-drug resistant ovarian cancer cells via impairing the AKT/GSK3β/β-catenin signaling, providing a promising therapeutic strategy for a successful treatment of ovarian cancer.