Mitochondrial defects and Cancer Therapeutics

线粒体缺陷和癌症治疗

• 批准号: 7092189
• 负责人: Peng Huang
• 金额: $ 30.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-07 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092189
• 关键词: DNA damage; antineoplastics; bioenergetics; cell line; cellular respiration; clinical research; drug resistance; enzyme activity; free radical oxygen; gene mutation; glycolysis; mitochondrial DNA; mitochondrial disease /disorder; molecular oncology; neoplasm /cancer genetics; neoplastic cell; neoplastic transformation; oxidative phosphorylation; oxidative stress; phosphatidylinositol 3 kinase; phosphorylation; serine threonine protein kinase

DESCRIPTION (provided by applicant): It has long been recognized that cancer cells and normal cells have different energy metabolic patterns. One longstanding 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 (mtDNA) 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.

描述（申请人提供）：人们很早就认识到癌细胞和正常细胞具有不同的能量代谢模式。一个长期而突出的观察是，即使在氧气供应充足的情况下，癌细胞也会表现出糖酵解增加，这种现象被称为瓦伯格效应。尽管在多种人类癌症中一致观察到 ATP 供应对糖酵解的依赖性增加，但导致这种代谢改变的生化和分子机制及其治疗意义仍有待阐明。包括我们实验室在内的多个小组最近的研究表明，线粒体 DNA (mtDNA) 在人类癌细胞中经常发生突变，与药物敏感性的改变有关。由于线粒体在 ATP 产生和细胞凋亡中都发挥着重要作用，我们假设线粒体 DNA 突变和随之而来的线粒体呼吸链功能障碍，通过氧化磷酸化导致 ATP 产生减少，迫使恶性细胞增加糖酵解以维持能量供应，并诱导细胞存活信号和药物敏感性的改变。我们将利用生化和分子生物学方法研究以下具体目标：（1）研究mtDNA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来检验以下假设：由内源性 ROS 应激和外源性 DNA 损伤剂引起的线粒体 DNA 突变会导致线粒体呼吸功能障碍、对糖酵解的依赖性增加以及超氧化物生成增加。来自患者的原代癌细胞将用于测试该假设的临床相关性。 (2) 研究 mtDNA 突变在改变细胞存活和药物敏感性中的作用。我们将描述具有线粒体突变的细胞中药物反应的特征，并确定在杀死具有线粒体呼吸缺陷的癌细胞方面有效或无效的抗癌药物。将建立含有正常或突变线粒体的细胞的明确实验模型系统，以进一步测试线粒体DNA突变与药物敏感性之间的因果关系，并研究其潜在机制。 （3）设计和测试针对癌细胞代谢缺陷和相关生存机制的新策略，以优先杀死恶性细胞。我们将测试新型药物抑制糖酵解、优先消耗癌细胞中 ATP 供应并导致细胞死亡的能力。我们还将开发抑制癌细胞生存途径的策略，并探索利用ROS介导的机制根据与mtDNA突变相关的氧化应激增加来优先杀死癌细胞的可能性。我们希望这项研究能够为癌细胞的基本代谢改变提供新的机制见解，并提供选择性和有效杀死癌细胞的新治疗策略。