The Nrf2/PGC1α Pathway Regulates Antioxidant and Proteasomal Activity to Alter Cisplatin Sensitivity in Ovarian Cancer.

Xinyue Deng,Jing Su,Long Xu,Haoge Luo,Yao Jin,Nan Lin,Yanan Liu,Jiaying Fu,Liankun Sun,Li Yang

doi:10.1155/2020/4830418

Abstract

Drug resistance remains a barrier in the clinical treatment of ovarian cancer. Proteasomal and antioxidant activities play important roles in tumor drug resistance, and increasing evidence suggests the existence of an interaction between antioxidant and proteasomal activities. However, the mechanism of the synergistic effects of proteasomal activity and antioxidation on tumor drug resistance is not completely clear. In this study, we compared two ovarian cancer cells, A2780 and SKOV3 cells. Among them, SKOV3 cell is a human clear cell carcinoma cell line that is resistant to platinum. We found that compared with the findings in A2780 cells, SKOV3 cells were less sensitive to both proteasomal inhibitor and cisplatin. Proteasomal inhibition enhanced the sensitivity of A2780 cells, but not SKOV3 cells, to cisplatin. Notably, the Nrf2-mediated antioxidant pathway was identified as a resistance mechanism in proteasome inhibitor-resistant cells, but this was not the only factor identified in our research. In SKOV3 cells, PGC1α regulated the antioxidant activity of Nrf2 by increasing the phosphorylation of GSK3β, and in turn, Nrf2 regulated the transcriptional activity of PGC1α. Thus, Nrf2 and PGC1α synergistically participate in the regulation of proteasomal activity. Furthermore, the Nrf2/PGC1α pathway participated in the regulation of mitochondrial function and homeostasis, further regulating proteasomal activity in SKOV3 cells. Therefore, exploring the roles of PGC1α and Nrf2 in the regulation of proteasomal activity by antioxidant and mitochondrial functions may provide new avenues for reversing drug resistance in ovarian cancer.

Highlights

Ovarian cancer is the most deadly gynecological malignancy, and drug resistance has become a major challenge in its treatment in recent years
The MTT assay illustrated that compared with the findings in SKOV3 cells, the proteasome inhibitor Epox decreased the viability of A2780 cells in a concentration-dependent manner (Figure 1(a))
The results demonstrated that Epox increased the sensitivity of A2780 cells, but not SKOV3

Summary

Introduction

Ovarian cancer is the most deadly gynecological malignancy, and drug resistance has become a major challenge in its treatment in recent years. Current research suggests that exploring the mechanisms of the interaction between different signals can shed light on the mechanisms of tumor drug resistance. The proteasome can eliminate oxidative and damaged proteins to reduce oxidative stress damage, and enhanced antioxidant capacity can promote the expression of 20S and 19S proteasome subunits [7, 8]. These findings suggest the existence of an interaction between proteasomal activity and redox function, and exploring this relationship will be more helpful in solving the problem of chemotherapy resistance in ovarian cancer

Methods

Results

Conclusion