Mitochondrial metabolism and ROS regulate cancer

线粒体代谢和 ROS 调节癌症

• 批准号: 10414889
• 负责人: NAVDEEP S CHANDEL
• 金额: $ 89.61万
• 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/10414889
• 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; anti-cancer; 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）：肿瘤细胞重新编程其细胞代谢，以维持细胞增殖增加的代谢需求。肿瘤细胞分裂成两个子细胞涉及脂质、蛋白质和核苷酸以及ATP和NADPH的从头合成。从历史上看，糖酵解作为肿瘤细胞代谢的重要中心代谢途径受到了广泛关注。在过去的几年里，我们提供了遗传学和药理学证据，证明除了葡萄糖代谢外，线粒体代谢对癌细胞增殖和肿瘤发生是必要的。线粒体代谢具有三种不同的功能，对癌细胞增殖和存活至关重要。首先，线粒体在大多数癌细胞中产生大部分ATP（生物能）。其次，线粒体三羧酸（TCA）循环中间体是生物合成大分子如脂质和核苷酸的前体。第三，线粒体产生高水平的活性氧（ROS），通过未鉴定的机制激活近端促肿瘤发生信号通路。为了补偿较高的ROS产生速率，癌细胞已经进化出适应性机制来增加细胞的抗氧化特性，从而维持还原型谷胱甘肽和硫氧还蛋白的库。这允许癌细胞使用ROS来激活刺激肿瘤细胞行为的近端信号传导途径，同时修复由ROS在旁观者大分子中引起的附带氧化损伤，否则会诱导癌细胞死亡或衰老。最近，我们证明了双胍二甲双胍，一种广泛使用的抗糖尿病药物，通过抑制线粒体复合物I通过不完全理解的机制减少裸鼠中人癌细胞的肿瘤生长。此外，线粒体靶向抗氧化剂也可以减少肿瘤生长。目前的资助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。

项目成果

Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation.

• DOI: 10.1371/journal.pbio.2005707
• 发表时间: 2018-04
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Lozoya OA;Martinez-Reyes I;Wang T;Grenet D;Bushel P;Li J;Chandel N;Woychik RP;Santos JH
• 通讯作者: Santos JH

Beyond ATP, new roles of mitochondria.

• DOI: 10.1042/bio_2022_119
• 发表时间: 2022-08
• 期刊: The biochemist

Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate.

• DOI: 10.1016/j.stem.2021.02.011
• 发表时间: 2021-03-04
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Chakrabarty RP;Chandel NS
• 通讯作者: Chandel NS

Acetyl-CoA-directed gene transcription in cancer cells.

• DOI: 10.1101/gad.315168.118
• 发表时间: 2018-04-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Martínez-Reyes I;Chandel NS
• 通讯作者: Chandel NS

DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.

• DOI: 10.1016/j.celrep.2022.111278
• 发表时间: 2022-08-30
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Yuskaitis, Christopher J.;Modasia, Jinita B.;Schrotter, Sandra;Rossitto, Leigh-Ana;Groff, Karenna J.;Morici, Christopher;Mithal, Divakar S.;Chakrabarty, Ram P.;Chandel, Navdeep S.;Manning, Brendan D.;Sahin, Mustafa
• 通讯作者: Sahin, Mustafa