Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission.
Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission.
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DOI：
10.3389/fonc.2022.893396
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发表时间：
2022
影响因子：
4.7
通讯作者：
Bueeler, Hansruedi
中科院分区：
文献类型：
--
作者：
Zhu, Dantong;Han, Fengtong;Sun, Liuke;Agnihotri, Sandeep K.;Hu, Ying;Bueeler, Hansruedi
关键词：
线粒体代谢和动力学（裂变和融合）对细胞存活和增殖起着至关重要的调节作用，这些途径的异常与神经退行性疾病和癌症都有关系。线粒体分裂是突变ras依赖性肿瘤生长所必需的。在这里，我们研究了pten诱导的激酶1 （PINK1）——一种与隐性家族性帕金森病相关的线粒体激酶——的缺失是否会影响ras诱导的致癌肿瘤的生长，无论在体内还是体外。我们发现，与野生型小鼠的rasg12d转化的胚胎成纤维细胞（mef）相比，来自pink1缺陷小鼠的rasg12d转化的胚胎成纤维细胞（mef）在软琼脂和裸鼠中的生长减少，坏死增加，细胞周期进展减慢。PINK1的再表达（过表达）至少部分地挽救了这些表型。PINK1缺失和PINK1过表达均未改变Ras表达水平。有趣的是，pink1缺陷的ras转化的mef表现出线粒体延长和DRP1磷酸化的改变，这是调节线粒体裂变的关键事件。DRP1的抑制降低了PINK1调控的线粒体形态变化和肿瘤生长，表明PINK1缺乏主要通过干扰线粒体分裂和相关的细胞坏死和细胞周期缺陷来抑制ras驱动的肿瘤生长。此外，我们证实了PINK1对ras转化细胞的最佳生长的要求，通过CRISPR/ cas9引入的PINK1基因缺失的人HCT116结肠癌细胞（携带内源性RasG13D突变）也显示出线粒体裂变减少和生长下降。我们的研究结果支持线粒体功能和动力学在调节ras依赖性肿瘤细胞生长中的重要性，并为帕金森病和其他神经退行性疾病中癌症发病率较低的可能机制提供了见解。
Mitochondrial metabolism and dynamics (fission and fusion) critically regulate cell survival and proliferation, and abnormalities in these pathways are implicated in both neurodegenerative disorders and cancer. Mitochondrial fission is necessary for the growth of mutant Ras-dependent tumors. Here, we investigated whether loss of PTEN-induced kinase 1 (PINK1) - a mitochondrial kinase linked to recessive familial Parkinsonism - affects the growth of oncogenic Ras-induced tumor growth in vitro and in vivo. We show that RasG12D-transformed embryonic fibroblasts (MEFs) from PINK1-deficient mice display reduced growth in soft agar and in nude mice, as well as increased necrosis and decreased cell cycle progression, compared to RasG12D-transformed MEFs derived from wildtype mice. PINK1 re-expression (overexpression) at least partially rescues these phenotypes. Neither PINK1 deletion nor PINK1 overexpression altered Ras expression levels. Intriguingly, PINK1-deficient Ras-transformed MEFs exhibited elongated mitochondria and altered DRP1 phosphorylation, a key event in regulating mitochondrial fission. Inhibition of DRP1 diminished PINK1-regulated mitochondria morphological changes and tumor growth suggesting that PINK1 deficiency primarily inhibits Ras-driven tumor growth through disturbances in mitochondrial fission and associated cell necrosis and cell cycle defects. Moreover, we substantiate the requirement of PINK1 for optimal growth of Ras-transformed cells by showing that human HCT116 colon carcinoma cells (carrying an endogenous RasG13D mutation) with CRISPR/Cas9-introduced PINK1 gene deletions also show reduced mitochondrial fission and decreased growth. Our results support the importance of mitochondrial function and dynamics in regulating the growth of Ras-dependent tumor cells and provide insight into possible mechanisms underlying the lower incidence of cancers in Parkinson’s disease and other neurodegenerative disorders.
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DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
影响因子：
3.7
作者：
Akundi RS;Huang Z;Eason J;Pandya JD;Zhi L;Cass WA;Sullivan PG;Büeler H
通讯作者：
Büeler H
DOI：
10.1073/pnas.0607260103
发表时间：
2006-10-10
影响因子：
11.1
作者：
Clements, Casey M.;McNally, Richard S.;Ting, Jenny P-Y.
通讯作者：
Ting, Jenny P-Y.
影响因子：
4.4
作者：
Garza-Lombo, Carla;Pappa, Aglaia;Franco, Rodrigo
通讯作者：
Franco, Rodrigo
影响因子：
10.3
作者：
Hu, Hui-Han;Kannengiesser, Caroline;Soufir, Nadem
通讯作者：
Soufir, Nadem