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

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.

ROS-Induced DCTPP1 Upregulation Contributes to Cisplatin Resistance in Ovarian Cancer

“…Nrf2 is a key redox regulator. HO-1 and GCLC are located downstream of Nrf2 and play important roles in intracellular redox balance as antioxidant enzymes ( Bao et al, 2014 ; Silva et al, 2019 ; Deng et al, 2020 ; Ghosh et al, 2021 ). Some reports showed the balance between Nrf2/GSH antioxidant pathway and DNA repair might modulate cisplatin resistance in cancer cells ( Qiu et al, 2020 ; Ghosh et al, 2021 ).…”

Insights into the Role of Oxidative Stress in Ovarian Cancer

“…Many studies have confirmed the important role of redox modification of signaling pathways in the pathogenesis of OC, including the Keap1-Nrf2-ARE, PI3K/AKT/mTOR, Wnt/β-catenin, and Notch pathways [100][101][102][103].…”

“…In addition, inhibiting the production of proteasomes promotes the translocation of Nrf2 into the nucleus via the Keap1/Nrf2 pathway, resulting in drug resistance in OC cells. Nrf2 and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) can synergistically regulate antioxidant functions and mitochondrial functions, thus regulating the maintenance of proteasome activity and affecting the sensitivity of OC cells to chemotherapy agents [101]. Oxidative Medicine and Cellular Longevity…”

Exploring the Antiglioma Mechanisms of Luteolin Based on Network Pharmacology and Experimental Verification

“…The measured values were expressed as a ratio by comparing them to the control group values. More details for WB and sqRT-PCR were described previously [ 36 ]. In brief, cells were lysed in radio immunoprecipitation assay (RIPA) lysis buffer (P0013B, Beyotime).…”