Shen Feifei, Gai Junda, Xing Jilin, Guan Jingqian, Fu Lin, Li Qingchang
Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Biochem Biophys Res Commun. 2018 Jan 1;495(1):1158-1166. doi: 10.1016/j.bbrc.2017.11.109. Epub 2017 Nov 22.
Lung cancer is the leading cause of cancer death worldwide, and most of all cases are non-small-cell lung cancer. Lung cancer is associated with dysregulation of mitochondrial fusion and fission, and inhibition of the fission regulator Dynamin-related protein 1 (Drp1) reduces proliferation and increases apoptosis of lung cancer cells. Dynasore is a small molecule non-selective inhibitor of the GTPase activity of dynamin 1, dynamin 2, and Drp1 in vivo and in vitro. Here, we investigated the effects of dynasore on the proliferation and apoptosis of A549 lung cancer cells, alone and in combination with the chemotherapeutic drug cisplatin. We found that cisplatin increased mitochondrial fission and dynamin 2 expression, whereas dynasore had the opposite effects. However, both cisplatin and dynasore independently induced mitochondrial oxidative stress, leading to mitochondrial dysfunction, reduced cell proliferation, and enhanced apoptosis. Importantly, dynasore significantly augmented the anti-cancer effects of cisplatin. To the best of our knowledge, this is the first report that dynasore inhibits proliferation and induces apoptosis of lung cancer cells, and enhances the inhibitory effects of cisplatin.
肺癌是全球癌症死亡的主要原因，并且大多数病例为非小细胞肺癌。肺癌与线粒体融合和裂变的失调相关，抑制裂变调节因子动力相关蛋白1（Drp1）可减少肺癌细胞的增殖并增加其凋亡。Dynasore是一种在体内和体外对动力蛋白1、动力蛋白2和Drp1的GTPase活性具有非选择性抑制作用的小分子。在此，我们研究了Dynasore单独以及与化疗药物顺铂联合使用时对A549肺癌细胞增殖和凋亡的影响。我们发现顺铂增加了线粒体裂变和动力蛋白2的表达，而Dynasore则具有相反的作用。然而，顺铂和Dynasore均可独立诱导线粒体氧化应激，导致线粒体功能障碍、细胞增殖减少和凋亡增加。重要的是，Dynasore显著增强了顺铂的抗癌作用。据我们所知，这是关于Dynasore抑制肺癌细胞增殖、诱导其凋亡并增强顺铂抑制作用的首次报道。
