K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis.
K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis.
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有氧糖酵解和氧化应激增加是癌细胞代谢的重要特征，但其潜在的生化和分子机制仍不清楚。使用四环素诱导的模型，我们发现K-rasG12V的激活导致线粒体功能障碍，导致呼吸减少，糖酵解升高，以及活性氧的产生增加。K-RAS蛋白与线粒体有关，通过影响对环孢素敏感的通透性转换孔，导致呼吸链复合体-I的快速抑制和线粒体跨膜电位的降低。此外，在体外预先诱导K-rasG12V表达，以允许代谢适应高糖酵解代谢，可增强转化细胞在体内形成肿瘤的能力。我们的研究表明，诱导线粒体功能障碍是K-rasG12V引起肿瘤细胞代谢改变和ROS应激，促进肿瘤发生的重要机制。
Increased aerobic glycolysis and oxidative stress are important features of cancer cell metabolism, but the underlying biochemical and molecular mechanisms remain elusive. Using a tetracycline inducible model, we show that activation of K-rasG12V causes mitochondrial dysfunction, leading to decreased respiration, elevated glycolysis, and increased generation of reactive oxygen species. The K-RAS protein is associated with mitochondria, and induces a rapid suppression of respiratory chain complex-I and a decrease in mitochondrial transmembrane potential by affecting the cyclosporin-sensitive permeability transition pore. Furthermore, pre-induction of K-rasG12V expression in vitro to allow metabolic adaptation to high glycolytic metabolism enhances the ability of the transformed cells to form tumor in vivo. Our study suggests that induction of mitochondrial dysfunction is an important mechanism by which K-rasG12V causes metabolic changes and ROS stress in cancer cells, and promotes tumor development.
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