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.
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