PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma
PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma
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DOI：
10.1158/0008-5472.can-15-3079
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发表时间：
2016-08-15
期刊：
影响因子：
11.2
通讯作者：
Rutka, James T.
中科院分区：
文献类型：
--
作者：
Agnihotri, Sameer;Golbourn, Brian;Rutka, James T.
增殖癌细胞的特点是糖酵解速率高，乳酸产生，线粒体代谢改变。这种代谢重编程为肿瘤细胞（包括胶质母细胞瘤）的增殖提供了重要的代谢物。然而，这些生物过程产生氧化应激，必须通过活性氧（ROS）的解毒来平衡。在未转化的人类星形胶质细胞中使用无偏倚逆转录病毒功能丧失筛查，我们证明线粒体pten诱导的激酶1 （PINK1）是Warburg效应的调节剂和胶质母细胞瘤生长的负调节剂。我们报道，PINK1的缺失通过ros依赖的缺氧诱导因子- 1a的稳定和丙酮酸激酶肌肉同工酶2活性的降低有助于Warburg效应，两者都是有氧糖酵解的关键调节因子。从机制上讲，PINK1通过氧化应激和超氧化物歧化酶2的主要调节因子FOXO3a抑制ROS和肿瘤生长。这些发现强调了正常和肿瘤细胞中PINK1和ROS平衡的重要性。PINK1缺失在包括胶质母细胞瘤在内的大量人脑肿瘤中被观察到（n bbb900），并与患者生存率低相关。在原位小鼠异种移植模型和果蝇转基因胶质母细胞瘤模型中，PINK1过表达可减弱体内胶质母细胞瘤的生长。(c) 2016年aacr。
Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila. (C) 2016 AACR.