Zou Guang-Ping, Yu Chun-Xia, Shi Sheng-Lan, Li Qiu-Gen, Wang Xiao-Hua, Qu Xin-Hui, Yang Zhang-Jian, Yao Wei-Rong, Yan Dan-Dan, Jiang Li-Ping, Wan Yu-Ying, Han Xiao-Jian
Institute of Geriatrics, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
J Cancer. 2021 Oct 28;12(24):7358-7373. doi: 10.7150/jca.61379. eCollection 2021.
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.
顺铂（DDP）是卵巢癌的一线化疗药物。然而，顺铂耐药的产生严重影响了卵巢癌的化疗效果和预后。据报道，顺铂可直接作用于线粒体并激活内源性凋亡途径。在此，研究了线粒体动力学在人卵巢癌SKOV3细胞顺铂耐药中的作用。在顺铂耐药的SKOV3/DDP细胞中，线粒体分裂蛋白DRP1下调，而线粒体融合蛋白MFN2上调。与DRP1和MFN2的表达一致，SKOV3/DDP细胞中线粒体的平均长度显著增加。在顺铂敏感的亲本SKOV3细胞中，在顺铂应激下第2至6天发生了DRP1的下调以及包括MFN1、2和OPA1在内的线粒体融合蛋白的上调。敲低DRP1或过表达MFN2可促进SKOV3细胞对顺铂的耐药性。有趣的是，在SKOV3/DDP细胞中检测到较弱的迁移能力和较低的ATP水平。使用小干扰RNA分别敲低亲本SKOV3细胞中的DRP1或SKOV3/DDP细胞中的MFN2可有效逆转线粒体动力学、迁移能力和ATP水平。此外，MFN2小干扰RNA显著加重了顺铂诱导的SKOV3/DDP细胞中ROS的产生、线粒体膜电位的破坏、促凋亡蛋白BAX的表达以及半胱天冬酶-3/9的裂解。相反，DRP1小干扰RNA减轻了顺铂诱导的SKOV3细胞中ROS的产生、线粒体膜电位的破坏、促凋亡蛋白BAX的表达以及半胱天冬酶-3/9的裂解。因此，这些结果表明，由DRP1和MFN2介导的线粒体动力学促进了卵巢癌细胞顺铂耐药的产生，也将为通过靶向线粒体动力学预防卵巢癌化疗耐药提供一种新策略。
