Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells

Abstract

Cisplatin (DDP) is the first-line chemotherapeutic agent for ovarian cancer. However, the development of DDP resistance seriously influences the chemotherapeutic effect and prognosis of ovarian cancer. It was reported that DDP can directly impinge on the mitochondria and activate the intrinsic apoptotic pathway. Herein, the role of mitochondrial dynamics in DDP chemoresistance in human ovarian cancer SKOV3 cells was investigated. In DDP-resistant SKOV3/DDP cells, mitochondrial fission protein DRP1 was down-regulated, while mitochondrial fusion protein MFN2 was up-regulated. In accordance with the expression of DRP1 and MFN2, the average mitochondrial length was significantly increased in SKOV3/DDP cells. In DDP-sensitive parental SKOV3 cells, downregulation of DRP1 and upregulation of mitochondrial fusion proteins including MFN1,2 and OPA1 occurred at day 2~6 under cisplatin stress. Knockdown of DRP1 or overexpression of MFN2 promoted the resistance of SKOV3 cells to cisplatin. Intriguingly, weaker migration capability and lower ATP level were detected in SKOV3/DDP cells. Respective knockdown of DRP1 in parental SKOV3 cells or MFN2 in SKOV3/DDP cells using siRNA efficiently reversed mitochondrial dynamics, migration capability and ATP level. Moreover, MFN2 siRNA significantly aggravated the DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3/DDP cells. In contrast, DRP1 siRNA alleviated DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3 cells. Thus, these results indicate that mitochondrial dynamics mediated by DRP1 and MFN2 contributes to the development of DDP resistance in ovarian cancer cells, and will also provide a new strategy to prevent chemoresistance in ovarian cancer by targeting mitochondrial dynamics.

Ovarian Cancer: A Landscape of Mitochondria with Emphasis on Mitochondrial Dynamics

“…In SKOV3 cisplatin-resistant cells, the mitochondrial fission protein DRP1 is down-regulated, while the mitochondrial fusion protein MFN2 is up-regulated. In accordance with the expression of DRP1 and MFN2, the average mitochondrial length was significantly increased in these cells, supporting again that mitochondrial dynamics contribute to the development of cisplatin resistance in ovarian cancer cells [ 122 ]. This was also shown by the silencing of DRP1 or overexpression of MFN2 that promote the resistance of SVOK3 cells to cisplatin [ 122 ].…”

“…In accordance with the expression of DRP1 and MFN2, the average mitochondrial length was significantly increased in these cells, supporting again that mitochondrial dynamics contribute to the development of cisplatin resistance in ovarian cancer cells [ 122 ]. This was also shown by the silencing of DRP1 or overexpression of MFN2 that promote the resistance of SVOK3 cells to cisplatin [ 122 ]. In addition, the pro-fission activity of DRP1, as mentioned before, depends on its phosphorylation status.…”

Metformin-induced AMPK activation promotes cisplatin resistance through PINK1/Parkin dependent mitophagy in gastric cancer

“…Previous studies have suggested that mitochondrial dynamics could influence chemotherapy sensitivity in cancer cells. In our previous studies, it was found that mitochondrial dynamics participate in cisplatin resistance in ovarian cancer, and the level of mitochondrial fusion was higher in cisplatin resistant ovarian cancer cells ( 43 ). However, the contrary results were obtained in GC cells, as increased mitochondrial fission was observed in SGC-7901/DDP cells compared with that in SGC-7901 cells.…”

Low expression of MYCN promotes cisplatin resistance by suppressing cisplatin‑induced apoptosis in epithelial ovarian cancer

“…Cells and cell culture. The human EOC SK-OV-3 cell line, which is commonly used in the study of cisplatin-resistant in serous EOC (29,30), was purchased from Jiangsu KeyGEN BioTECH Co., Ltd. The human EOC cisplatin-resistant SK-OV-3/DDP cell line was purchased from Shanghai Chuan Qiu Biotechnology Co., Ltd.…”