Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling

Lan Yin,Liaotian Peng,Ye Zhao,Zhengyu Han,Wanglong Zhu,Yu Xian,Yuhan Yang,Kun Zhang,Houyi Huang

doi:10.3389/fonc.2021.620907

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.

Highlights

Ovarian cancer is one of the most prevalent female reproductive organ malignancies and the major cause of gynecological malignancy-related mortality [1], primarily treated with surgery and chemotherapy [2, 3]
To examine whether Heat shock protein 90 (Hsp90) is involved in ovarian cancer resistance, paclitaxel- and cisplatin-resistant ovarian cancer cells (A2780/Taxol and A2780/CDDP), and their parental cells A2780 were used in this study
The western blotting results showed that the protein expression of Hsp90 was significantly increased in A2780/Taxol and A2780/CDDP cells, compared with A2780 cells (Figures 1A,B), suggesting that Hsp90 was related to the resistance of ovarian cancer cells to paclitaxel and cisplatin

Summary

Introduction

Ovarian cancer is one of the most prevalent female reproductive organ malignancies and the major cause of gynecological malignancy-related mortality [1], primarily treated with surgery and chemotherapy [2, 3]. Cancer patients who are resistant to chemotherapy often exhibit high expression of various ABC transporter efflux pumps including, multi-drug resistance protein 1 (P-gp/MDR1), MDRassociated protein 1 and breast cancer resistance protein (BCRP) [17, 18], the ABC transporter family members requiring ATP hydrolysis to efflux substrates and cytotoxic substances from cells [19]. Previous studies revealed that Survivin and Bcl-2 upregulation can suppress the anti-cancer drug-induced apoptosis in a series of cancers, such as ovarian, breast, and lung cancer [22,23,24]. Cancer cells undergoing MDR were generally characterized by ectopic alteration of various pathways including PI3K/AKT and Wnt/β-catenin, which play an import role in the expression of ABC transporter and anti-apoptosis protein such as P-gp, BCRP, Survivin and Bcl-2 [25,26,27,28,29,30]

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