title: Malate-aspartate shuttle inhibitor aminooxyacetic acid leads to decreased intracellular ATP levels and altered cell cycle of C6 glioma cells by inhibiting glycolysis.
abstract: NADH shuttles, including malate-aspartate shuttle (MAS) and glycerol-3-phosphate shuttle, can shuttle the reducing equivalents of cytosolic NADH into mitochondria. It is widely accepted that the major function of NADH shuttles is to increase mitochondrial energy production. Our study tested the hypothesis that the novel major function of NADH shuttles in cancer cells is to maintain glycolysis by decreasing cytosolic NADH/NAD(+) ratios. We found that AOAA, a widely used MAS inhibitor, led to decreased intracellular ATP levels, altered cell cycle and increased apoptosis and necrosis of C6 glioma cells, without affecting the survival of primary astrocyte cultures. AOAA also decreased the glycolytic rate and the levels of extracellular lactate and pyruvate, without affecting the mitochondrial membrane potential of C6 cells. Moreover, the toxic effects of AOAA were completely prevented by pyruvate treatment. Collectively, our study has suggested that AOAA may be used to selectively decrease glioma cell survival, and the major function of MAS in cancer cells may be profoundly different from its major function in normal cells: The major function of MAS in cancer cells is to maintain glycolysis, instead of increasing mitochondrial energy metabolism.
authors.affiliation: Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Wang
authors.affiliation: Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Heyu
authors.initials: H
authors.lastname: Chen
authors.affiliation: Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Xunbin
authors.initials: X
authors.lastname: Wei
authors.affiliation: Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: weihaiy@sjtu.edu.cn.
authors.forename: Weihai
authors.initials: W
authors.lastname: Ying
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001224:Aspartic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects*; D008293:Malates / Q000378:metabolism*; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis; D061251:Primary Cell Culture; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008293:Malates; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D000625:Aminooxyacetic Acid; D001224:Aspartic Acid; C030298:malic acid; D000255:Adenosine Triphosphate
keywords: Cell cycle; Mitochondria; Pyruvate