Mitochondrial defects and Cancer Therapeutics

长期以来，人们已经认识到癌细胞和正常细胞具有不同的能量代谢模式。一个长- 长期和突出的观察是，即使在存在足够的糖酵解的情况下，癌细胞也显示出糖酵解增加。 氧气供应，一种被称为瓦尔堡效应的现象。虽然对糖酵解的依赖性增加， 在广泛的人类癌症中一直观察到供应，生物化学和分子生物学， 负责这种代谢改变的机制及其治疗意义仍有待阐明。 包括我们实验室在内的几个研究小组最近的研究表明，线粒体DNA（莫纳）经常被 在人类癌细胞中发生突变，与药物敏感性的改变有关。因为线粒体在这一过程中 在ATP产生和细胞凋亡中的作用，我们假设线粒体DNA突变和随之而来的 线粒体呼吸链的功能障碍导致ATP的产生减少，通过氧化 磷酸化，迫使恶性细胞增加糖酵解，以维持能量供应，并诱导改变， 细胞存活信号传导和药物敏感性。我们将使用生物化学和分子生物学方法来研究 具体目标如下：（1）研究线粒体DNA突变作为能量代谢改变的遗传基础。我们 将建立创新的实验系统，以测试这一假设，即线粒体DNA突变，由两个 内源性ROS应激和外源性DNA损伤剂，导致线粒体呼吸功能障碍， 增加对糖酵解的依赖性，并增加超氧化物的产生。来自患者的原发癌细胞将被 用于检验该假设的临床相关性。(2)研究mtDNA突变在改变细胞中的作用 存活率和药物敏感性。我们将描述线粒体突变细胞中药物反应的特征， 并鉴定在杀死具有线粒体的癌细胞方面有效或无效的抗癌剂， 呼吸缺陷将使用含有正常或突变线粒体的细胞的定义的实验模型系统， 建立了进一步测试mtDNA突变和药物敏感性之间的因果关系， 研究潜在的机制。(3)设计和测试针对癌症代谢缺陷的新策略 细胞和相关的生存机制，以优先杀死恶性细胞。我们将测试小说的能力 抑制糖酵解、优先消耗癌细胞中的ATP供应并导致细胞死亡的药剂。我们还将 开发抑制癌细胞中细胞存活途径的策略，并探索使用ROS介导的 基于与mtDNA相关的氧化应激增加，优先杀死癌细胞的机制 突变。我们希望这项研究将为基本的代谢改变提供新的机制见解 在癌细胞中，并提供新的治疗策略，以选择性和有效地杀死癌细胞。

It has long been recognized that cancer cells and normal cells have different energy metabolic patterns. One long- standing and prominent observation is that cancer cells show increased glycolysis even in the presence of the adequate oxygen supply, a phenomenon known as Warburg effect. Although the increased dependency on glycolysis for ATP supply has been observed consistently in a wide spectrum of human cancers, the biochemical and molecular mechanisms responsible for this metabolic alteration and its therapeutic implications remain to be elucidated. Recent studies by several groups, including our laboratory, showed that mitochondrial DNA (mONA) is frequently mutated in human cancer cells, associated with alterations in drug sensitivity. Because mitochondria play essential roles both in ATP production and apoptosis, we hypothesize that mitochondrial DNA mutations and the consequent malfunction of the mitochondrial respiratory chain lead to a decrease in ATP production through oxidative phosphorylation, forcing the malignant cells to increased glycolysis to maintain energy supply, and induce alterations in cell survival signaling and drug sensitivity. We will use biochemical and molecular biology methods to investigate the following specific aims: (1) Investigate mtDNA mutations as a genetic basis for alteration of energy metabolism. We will establish innovative experimental systems to test the hypothesis that mtDNA mutations, caused by both endogenous ROS stress and exogenous DNA-damaging agents, lead to malfunction of mitochondrial respiration, increased dependency on glycolysis, and increased superoxide generation. Primary cancer cells from patients will be used to test the clinical relevance of this hypothesis. (2) Investigate the role of mtDNA mutations in altering cell survival and drug sensitivity. We will characterize the profile of drug response in cells with mitochondrial mutations, and identify anticancer agents that are either effective or ineffective in killing cancer cells with mitochondrial respiration defects. Defined experimental model systems with cells containing normal or mutated mitochondria will be established to further test the cause-effect relationship between mtDNA mutations and drug sensitivity, and to investigate the underlying mechanisms. (3) Design and test novel strategies to target the metabolic defects in cancer cells and the associated survival mechanisms to preferentially kill the malignant cells. We will test the ability of novel agents to inhibit glycolysis, preferentially deplete ATP supply in cancer cells, and cause cell death. We will also develop strategies to inhibit cell survival pathways in cancer cells, and explore the possibility of using ROS-mediated mechanism to preferentially kill cancer cells based on their increased oxidative stress associated with mtDNA mutations. We hope that this research will provide new mechanistic insights into the fundamental metabolic alterations in cancer cells, and offer new therapeutic strategies to selectively and effectively kill cancer cells.