J Cancer 2021; 12(24):7358-7373. doi:10.7150/jca.61379 This issue

Research Paper

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

Guang-Ping Zou1,4*, Chun-Xia Yu5*, Sheng-Lan Shi1,4, Qiu-Gen Li1, Xiao-Hua Wang1, Xin-Hui Qu1,3, Zhang-Jian Yang5, Wei-Rong Yao6, Dan-Dan Yan5, Li-Ping Jiang5, Yu-Ying Wan2, Xiao-Jian Han1,3,4✉

1. Institute of Geriatrics, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
2. Department of Intra-hospital Infection Management, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
3. Department of Neurology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
4. Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
5. Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
6. Department of Oncology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
* These authors have contributed equally to this work.

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Citation:
Zou GP, Yu CX, Shi SL, Li QG, Wang XH, Qu XH, Yang ZJ, Yao WR, Yan DD, Jiang LP, Wan YY, Han XJ. Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells. J Cancer 2021; 12(24):7358-7373. doi:10.7150/jca.61379. Available from https://www.jcancer.org/v12p7358.htm

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Abstract

Graphic 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.

Keywords: ovarian cancer, mitochondrial dynamics, chemoresistance, cisplatin, apoptosis