Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma.
Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma.
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Drp1 介导的线粒体裂变通过 p53 和 NF-kappa B 通路的串扰促进肝细胞癌中的细胞增殖
DOI：
10.18632/oncotarget.11339
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Xing J
中科院分区：
文献类型：
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作者：
Zhan L;Cao H;Wang G;Lyu Y;Sun X;An J;Wu Z;Huang Q;Liu B;Xing J
线粒体是高度动态的，并且经历对于维持细胞的生理功能必不可少的恒定融合和分裂。最近，我们报道了线粒体分裂增加通过ROS介导的NF-κ B和p53通路的协同调节促进肝细胞癌（HCC）细胞的自噬和凋亡抵抗。然而，关于线粒体动力学在HCC细胞增殖中的作用知之甚少，这是癌细胞的另一个关键特征。在这项研究中，我们系统地研究了线粒体分裂在肝癌细胞增殖调节中的功能作用。此外，深入探讨了潜在的分子机制。我们发现，通过强制表达Drp1增加线粒体分裂促进肝癌细胞增殖在体外和体内主要是通过促进细胞周期的G1/S期转变。然而，在异种移植模型中，Drp1敲低或用线粒体分裂抑制剂-1处理诱导HCC细胞显著的G1期停滞并减少肿瘤生长。我们进一步证明Drp1介导的线粒体分裂的增殖促进作用是通过p53/p21和NF-κ B/cyclins途径介导的。此外，p53和NF-κ B通路之间的相互作用被证实参与了线粒体分裂介导的细胞增殖的调节。总之，我们的研究结果表明，Drp1介导的线粒体分裂在细胞周期进程和肝癌细胞增殖的调节中起着关键作用。因此，靶向Drp1依赖的线粒体分裂可能为抑制HCC的肿瘤生长提供新的策略。
Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Recently, we have reported that increased mitochondrial fission promotes autophagy and apoptosis resistance in hepatocellular carcinoma (HCC) cell through ROS-mediated coordinated regulation of NF-κB and p53 pathways. However, little is known about the roles of mitochondrial dynamics in HCC cell proliferation, another key feature of cancer cells. In this study, we systematically investigated the functional role of mitochondrial fission in the regulation of HCC cell proliferation. Furthermore, the underlying molecular mechanisms were deeply explored. We found that, increased mitochondrial fission by forced expression of Drp1 promoted the proliferation of HCC cells both in vitro and in vivo mainly by facilitating G1/S phase transition of cell cycle. Whereas, Drp1 knockdown or treatment with mitochondrial division inhibitor-1 induced significant G1 phase arrest in HCC cells and reduced tumor growth in the xenotransplantation model. We further demonstrated that the proliferation-promoting role of Drp1-mediated mitochondrial fission was mediated via p53/p21 and NF-κB/cyclins pathways. Moreover, the crosstalk between p53 and NF-κB pathways was proved to be involved in the regulation of mitochondrial fission-mediated cell proliferation. In conclusion, our findings demonstrate that Drp1-mediated mitochondrial fission plays a critical role in the regulation of cell cycle progression and HCC cell proliferation. Thus, targeting Drp1-dependent mitochondrial fission may provide a novel strategy for suppressing tumor growth of HCC.