Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Korea.
New Drug Development Center, Deagu-Gyeongbuk Medical Innovation Foundation, 80 Chembok-ro, Dong-gu, Daegu 41061, Korea.
Molecules. 2020 Dec 8;25(24):5793. doi: 10.3390/molecules25245793.
Mitochondrial fragmentation occurs during the apoptosis. Dynamin-related protein 1 (Drp1) acts as an important component in mitochondrial fission machinery and can regulate various biological processes including apoptosis, cell cycle, and proliferation. The present study demonstrates that dysfunction of mitochondrial dynamics plays a pivotal role in cisplatin-induced apoptosis. Inhibiting the mitochondrial fission with the specific inhibitor (Mdivi-1) did not affect apoptotic cell death in low concentrations (<10 μM). Interestingly, mdivi-1 enhanced cisplatin-induced apoptosis in cancer cells, but not in normal cells. Particularly in the presence of mdivi-1, several human cancer cell lines, including renal carcinoma cell line Caki-1, became vulnerable to cisplatin by demonstrating the traits of caspase 3-dependent apoptosis. Combined treatment induced downregulation of c-FLIP expression transcriptionally, and ectopic expression of c-FLIP attenuated combined treatment-induced apoptotic cell death with mdivi-1 plus cisplatin. Collectively, our data provide evidence that mdivi-1 might be a cisplatin sensitizer.
线粒体碎片化发生在细胞凋亡过程中。与动力蛋白相关的蛋白 1（Drp1）作为线粒体分裂机制中的重要组成部分，可以调节包括细胞凋亡、细胞周期和增殖在内的各种生物学过程。本研究表明，线粒体动力学功能障碍在顺铂诱导的细胞凋亡中起着关键作用。用特异性抑制剂（Mdivi-1）抑制线粒体分裂在低浓度（<10 μM）时不会影响细胞凋亡。有趣的是，mdivi-1 增强了顺铂诱导的癌细胞凋亡，但对正常细胞没有影响。特别是在 mdivi-1 的存在下，几种人类癌细胞系，包括肾癌细胞系 Caki-1，通过表现出 caspase 3 依赖性凋亡的特征，对顺铂变得敏感。联合治疗转录地下调 c-FLIP 的表达，并且 c-FLIP 的异位表达减弱了 mdivi-1 加顺铂联合治疗诱导的凋亡细胞死亡。总之，我们的数据提供了证据表明 mdivi-1 可能是顺铂增敏剂。
