Mitochondrial metabolism and ROS regulate cancer

线粒体代谢和 ROS 调节癌症

• 批准号: 9211296
• 负责人: NAVDEEP S CHANDEL
• 金额: $ 91.44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211296
• 关键词: Anabolism; Antidiabetic Drugs; Antioxidants; Attention; Biguanides; Bioenergetics; Cell Aging; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Metabolic Process; Citric Acid Cycle; Complex; Genetic; Glycolysis; Grant; Human; Lipids; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metformin; Mitochondria; NADP; Neoplasm Metastasis; Nucleotides; Nude Mice; Pharmacology; Production; Property; Proteins; Reactive Oxygen Species; Reduced Glutathione; Signal Pathway; TXN gene; Tumorigenicity; cancer cell; cell behavior; daughter cell; glucose metabolism; macromolecule; mitochondrial metabolism; neoplastic cell; oxidative damage; public health relevance; repaired; tumor growth; tumor metabolism; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): Tumor cells reprogram their cell metabolism to sustain the increased metabolic demands of cell proliferation. The division of a tumor cell into two daughter cells involves the de novo synthesis of lipids, proteins, and nucleotides as well as ATP and NADPH. Historically, much attention has focused on glycolysis as the central metabolic pathway important for tumor cell metabolism. In the past few years, we have provided genetic and pharmacologic evidence that mitochondrial metabolism in addition to glucose metabolism is necessary for cancer cell proliferation and tumorigenesis. Mitochondrial metabolism serves three distinct functions that are critical for cancer cell proliferation and survival. First, the mitochondria generate the majority of ATP (bioenergetic) in most cancer cells. Second, mitochondrial tricarboxylic acid (TCA) cycle intermediates are precursors for the biosynthesis of macromolecules such as lipids and nucleotides. Third, the mitochondria generate high levels of reactive oxygen species (ROS) to activate proximal pro-tumorigenic signaling pathways through unidentified mechanisms. To compensate for the higher rate of ROS production, cancer cells have evolved adaptive mechanisms to increase the antioxidant properties of the cells and thereby maintain the pools of reduced glutathione and thioredoxin. This permits cancer cells to use ROS to activate proximal signaling pathways that stimulate neoplastic cell behavior, while simultaneously repairing the collateral oxidative damage caused by ROS in bystander macromolecules that would otherwise induce cancer cell death or senescence. Recently, we demonstrated that the biguanide metformin, a widely used anti-diabetic drug, reduces the tumor growth of human cancer cells in nude mice by inhibiting mitochondrial complex I through not fully understood mechanisms. Furthermore, mitochondrial targeted antioxidants can also reduce tumor growth. The present grant will elucidate the underlying mechanisms by which mitochondrial metabolism and ROS is essential for tumor growth and metastasis.

 描述(由申请人提供)：肿瘤细胞重新编程它们的细胞代谢，以维持细胞增殖增加的代谢需求。肿瘤细胞分裂为两个子细胞，涉及脂质、蛋白质、核苷酸以及ATP和NADPH的从头合成。糖酵解作为肿瘤细胞代谢的重要中枢代谢途径，历来备受关注。在过去的几年里，我们已经提供了遗传学和药理学的证据，证明除了葡萄糖代谢外，线粒体代谢对于癌细胞的增殖和肿瘤的发生也是必要的。线粒体代谢有三种截然不同的功能，对癌细胞的增殖和存活至关重要。首先，在大多数癌细胞中，线粒体产生了大部分的ATP(生物能量)。其次，线粒体三羧酸(TCA)循环中间体是脂质和核苷酸等大分子生物合成的前体。第三，线粒体产生高水平的活性氧(ROS)，通过未知的机制激活近端的促肿瘤信号通路。为了弥补较高的ROS生成率，癌细胞已经进化出适应性机制，以增加细胞的抗氧化性能，从而维持还原型谷胱甘肽和硫氧还蛋白的池。这使得癌细胞可以利用ROS激活刺激肿瘤细胞行为的近端信号通路，同时修复旁观者大分子中ROS引起的并行氧化损伤，否则将导致癌细胞死亡或衰老。最近，我们证明了广泛使用的抗糖尿病药物双胍二甲双胍通过抑制线粒体复合体I而抑制人癌细胞在裸鼠体内的生长，其机制尚不完全清楚。此外，线粒体靶向抗氧化剂也可以减少肿瘤的生长。目前的拨款将阐明线粒体代谢和ROS对肿瘤生长和转移至关重要的潜在机制。