DNM1L型
MFN1型
线粒体分裂
生物
癌症研究
程序性细胞死亡
细胞凋亡
细胞生物学
自噬
线粒体
线粒体融合
线粒体DNA
生物化学
基因
作者
Qichao Huang,Lei Zhan,Haiyan Cao,Jibin Li,Yinghua Lyu,Xu Guo,Jing Zhang,Lele Ji,Tingting Ren,Jing An,Bing-Rong Liu,Yongzhan Nie,Jinliang Xing
出处
期刊:Autophagy
[Informa]
日期:2016-04-28
卷期号:12 (6): 999-1014
被引量:265
标识
DOI:10.1080/15548627.2016.1166318
摘要
Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.
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