Suppression of DRP1-mediated mitophagy increases the apoptosis of hepatocellular carcinoma cells in the setting of chemotherapy
Suppression of DRP1-mediated mitophagy increases the apoptosis of hepatocellular carcinoma cells in the setting of chemotherapy
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DOI：
10.3892/or.2020.7476
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发表时间：
2020-03-01
期刊：
影响因子：
4.2
通讯作者：
Chen, Rong-Xin
中科院分区：
文献类型：
--
作者：
Ma, Min;Lin, Xia-Hui;Chen, Rong-Xin
化疗对肝细胞癌（HCC）的疗效仍然不令人满意，主要是由于固有的自我防御机制（例如，线粒体自噬和自噬）。在本研究中，我们的目的是探讨靶向线粒体自噬的促凋亡作用，以增强肝癌化疗的疗效。肝癌细胞进行顺铂，顺铂诱导的线粒体自噬后，通过免疫荧光定量。用特异性动力蛋白相关蛋白1（dynamin-related protein 1，DRP 1）抑制剂Mdivi-1研究DRP 1在顺铂诱导的肝癌细胞线粒体自噬中的作用。在体外和体内评估顺铂和DRP 1抑制剂对HCC的协同作用。因此，顺铂通过激活DRP 1诱导存活的HCC细胞中的线粒体自噬。DRP 1抑制剂（Mdivi-1）通过靶向线粒体自噬增加顺铂处理的HCC细胞的凋亡。从机制上讲，Mdivi-1上调Bax和下调Bcl-xL，导致线粒体膜通透性增加，随后细胞色素c从线粒体释放到细胞质中，从而加重顺铂诱导的HCC细胞凋亡。此外，Mdivi-1与顺铂协同作用以抑制体内HCC异种移植物生长。我们的研究结果表明，靶向顺铂介导的线粒体自噬通过抑制DRP 1增加HCC细胞凋亡，为靶向线粒体自噬的联合治疗提供了临床前概念证据，以增强化疗的疗效。
The efficacy of chemotherapy for hepatocellular carcinoma (HCC) remains unsatisfactory, primarily due to inherent self-defense mechanisms (e.g., mitophagy and autophagy). In the present study, we aimed to explore the pro-apoptotic effects of targeting mitophagy to potentiate the efficacy of chemotherapy for HCC. HCC cells were subjected to cisplatin, after which cisplatin-induced mitophagy was quantified by immunofluorescence. Mdivi-1, a specific dynamin-related protein 1 (DRP1) inhibitor, was used to study the role of DRP1 in cisplatin-induced HCC mitophagy. The synergistic effect of cisplatin and the DRP1 inhibitor on HCC was assessed in vitro and in vivo. Accordingly, cisplatin induced mitophagy in surviving HCC cells by activating DRP1. The DRP1 inhibitor (Mdivi-1) increased the apoptosis of cisplatin-treated HCC cells by targeting mitophagy. Mechanistically, Mdivi-1 upregulated Bax and downregulated Bcl-xL, leading to an increase in mitochondrial membrane permeability and subsequent release of cytochrome c from mitochondria into the cytosol, thereby aggravating cisplatin-induced apoptosis in HCC cells. Moreover, Mdivi-1 acted synergistically with cisplatin to suppress HCC xenograft growth in vivo. Our results indicate that targeting cisplatin-mediated mitophagy increases HCC apoptosis via DRP1 inhibition, providing preclinical proof of concept for combination therapy targeting mitophagy to potentiate the efficacy of chemotherapy.