Mitochondrial metabolism and ROS regulate cancer

线粒体代谢和 ROS 调节癌症

基本信息

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
项目类别：
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

项目摘要

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（由应用提供）：肿瘤细胞重编程其细胞代谢，以维持细胞增殖的代谢需求增加。肿瘤细胞分为两个子细胞涉及从头合成脂质，蛋白质和核苷酸以及ATP和NADPH。从历史上看，许多关注集中在糖酵解作为对肿瘤细胞代谢重要的中心代谢途径上。在过去的几年中，我们提供了遗传和药理证据，即除葡萄糖代谢外，线粒体代谢除了葡萄糖代谢外，对于癌细胞增殖和肿瘤发生是必不可少的。线粒体代谢具有三种不同的功能，这对于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多数ATP（生物能）。其次，线粒体三核酸（TCA）循环中间体是大分子（例如脂质和核苷酸）生物合成的前体。第三，线粒体产生高水平的活性氧（ROS），通过未鉴定的机制激活近端促肿瘤信号通路。为了补偿较高的ROS产生率，癌细胞已经发展了适应性机制，以增加细胞的抗氧化特性，从而维持谷胱甘肽和硫氧还蛋白的减少池。这允许癌细胞使用ROS激活刺激肿瘤细胞行为的近端信号传导途径，同时修复旁观者大分子中ROS引起的附带氧化物损伤，否则会诱发癌细胞死亡或感受。最近，我们证明了Biguanide二甲双胍是一种广泛使用的抗糖尿病药物，通过通过未完全理解的机制抑制线粒体复合物I来降低裸鼠中人类癌细胞的肿瘤生长。此外，线粒体靶向抗氧化剂也可以减少肿瘤的生长。目前的赠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。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

Beyond ATP, new roles of mitochondria.

DOI：
10.1042/bio_2022_119
发表时间：
2022-08
期刊：
The biochemist
影响因子：
0
作者：
通讯作者：

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

Acetyl-CoA-directed gene transcription in cancer cells.