Zhu Dantong, Han Fengtong, Sun Liuke, Agnihotri Sandeep K, Hu Ying, Büeler Hansruedi
Harbin Institute of Technology, School of Life Science and Technology, Harbin, China.
Front Oncol. 2022 May 5;12:893396. doi: 10.3389/fonc.2022.893396. eCollection 2022.
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 and . We show that Ras-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 Ras-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 Ras mutation) with CRISPR/Cas9-introduced 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.
线粒体代谢与动态变化（分裂与融合）对细胞存活和增殖起着关键的调节作用，这些途径的异常与神经退行性疾病和癌症均有关联。线粒体分裂对于依赖突变型Ras的肿瘤生长是必需的。在此，我们研究了PTEN诱导激酶1（PINK1）——一种与隐性家族性帕金森病相关的线粒体激酶——的缺失是否会影响致癌性Ras诱导的肿瘤生长。我们发现，与源自野生型小鼠的Ras转化胚胎成纤维细胞（MEF）相比，来自PINK1缺陷小鼠的Ras转化MEF在软琼脂中和裸鼠体内生长减缓，坏死增加，细胞周期进程减慢。PINK1的重新表达（过表达）至少部分挽救了这些表型。PINK1的缺失和过表达均未改变Ras的表达水平。有趣的是，PINK1缺陷的Ras转化MEF表现出线粒体延长以及动力相关蛋白1（DRP1）磷酸化改变，这是调节线粒体分裂的关键事件。抑制DRP1可减少PINK1调节的线粒体形态变化和肿瘤生长，这表明PINK1缺陷主要通过干扰线粒体分裂以及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，我们通过显示经CRISPR/Cas9介导基因缺失的人HCT116结肠癌细胞（携带内源性Ras突变）也表现出线粒体分裂减少和生长减缓，证实了PINK1对于Ras转化细胞最佳生长的必要性。我们的结果支持了线粒体功能和动态变化在调节依赖Ras的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潜在机制提供了见解。
