Fan Zhongqi, Yu Huimei, Cui Ni, Kong Xianggui, Liu Xiaomin, Chang Yulei, Wu Yao, Sun Liankun, Wang Guangyi
Department of Hepatobiliary & Pancreas Surgery, The First Hospital, Jilin University, Changchun, Jilin 130021, China.
Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
Exp Cell Res. 2015 Jul 1;335(1):68-81. doi: 10.1016/j.yexcr.2015.04.016. Epub 2015 Apr 30.
Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60kD to 80kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics.
胆管癌对顺铂反应较弱。线粒体动力学参与对各种应激的反应，主要涉及线粒体自噬以及线粒体融合与裂变。Bcl-2家族蛋白在协调线粒体动力学中起关键作用，并参与对顺铂的耐药性。在此我们报告，ABT737与顺铂联合使用可促进胆管癌细胞发生凋亡。我们发现联合治疗降低了Mcl-1促生存形式并增加了Bak。接受顺铂治疗的细胞显示线粒体过度融合，而在接受联合治疗的细胞线粒体中碎片化占主导，Fis1水平更高，Mfn2和OPA1水平降低，Drp1 60kD与80kD形式的比例增加，且更多Drp1定位于线粒体。在具有碎片化线粒体的细胞中观察到更多p62聚集体，并且它们逐渐转位至线粒体。联合治疗诱导了线粒体自噬。敲低p62降低了Drp1比例，增加了Tom20，并提高了细胞活力。我们的数据表明线粒体动力学在胆管癌对顺铂的反应中起重要作用。ABT737可能通过调节线粒体动力学和Bcl-2家族蛋白内的平衡来增强胆管癌对顺铂的敏感性。此外，p62似乎在调节线粒体动力学中至关重要。
