Ma Min, Lin Xia-Hui, Liu Hua-Hua, Zhang Rui, Chen Rong-Xin
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
Oncol Rep. 2020 Mar;43(3):1010-1018. doi: 10.3892/or.2020.7476. Epub 2020 Jan 22.
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.
化疗对肝细胞癌（HCC）的疗效仍不尽人意，主要是由于其固有的自我防御机制（如线粒体自噬和自噬）。在本研究中，我们旨在探讨靶向线粒体自噬的促凋亡作用，以增强化疗对HCC的疗效。将HCC细胞用顺铂处理，然后通过免疫荧光对顺铂诱导的线粒体自噬进行定量。使用Mdivi-1（一种特异性的动力相关蛋白1（DRP1）抑制剂）来研究DRP1在顺铂诱导的HCC线粒体自噬中的作用。在体外和体内评估顺铂与DRP1抑制剂对HCC的协同作用。相应地，顺铂通过激活DRP1诱导存活的HCC细胞发生线粒体自噬。DRP1抑制剂（Mdivi-1）通过靶向线粒体自噬增加了顺铂处理的HCC细胞的凋亡。机制上，Mdivi-1上调Bax并下调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，在体内抑制HCC异种移植瘤的生长。我们的结果表明，靶向顺铂介导的线粒体自噬通过抑制DRP1增加HCC凋亡，为靶向线粒体自噬以增强化疗疗效的联合治疗提供了临床前概念验证。
