Abstract 985: Mitochondrial glutamine fermentation enhances ATP synthesis in murine glioblastoma cells

Abstract Otto Warburg first proposed that all cancer cells arise from irreversible impairment of respiration, thus requiring glucose fermentation as a compensatory energy source for maintaining viability. Glucose fermentation with lactate production in the presence of oxygen (aerobic glucose fermentation or the Warburg effect) is now recognized as a metabolic hallmark of nearly all cancers. Besides glucose, glutamine also serves as an energy metabolite for many cancer cells. It is not clear, however, how glutamine provides energy to cancer cells. We examined the influence of glucose and glutamine on ATP synthesis and viability in cultured mouse VM-M3 cells, a model for invasive human glioblastoma. The VM-M3 cells are known to have abnormal respiration. The cells were grown for 12 hrs or 24 hrs in “serum free minimal media” containing glucose alone (25 mM), glutamine alone (4.0 mM), or a combination of both energy metabolites. Using a bioluminescent-based in vitro ATP assay, we found that ATP production and cell viability was similar in VM-M3 cells grown in media containing either glutamine or glucose alone. Lactate production was significantly lower in VM-M3 cells grown in glutamine (0.24 mM) than in the cells grown in glucose (2.34 mM), indicating that these cells produce little lactate from glutamine alone. Robust synergy was found for ATP synthesis and lactate production when the cells were grown in both glucose and glutamine. Remarkably, the synergy persisted under anoxia (95% N2, 5% CO2) indicating that OxPhos did not play a major role in the synergistic interaction of glucose and glutamine. Preliminary [C13] NMR analysis showed that the cells grown in pan-labeled glutamine produced labeled succinate, aspartate, alanine, and citrate indicating that glutamine was metabolized through the TCA cycle in these cells. We propose that the glucose/glutamine energy synergy observed in the VM-M3 cells arises from linked fermentation redox couples in the cytoplasm and mitochondria that synthesize ATP largely through non-oxidative substrate level phosphorylations and possibly from an anaerobic electron transfer-based ATP synthesis at the level of fumarate reductase. In other words, the cells appear to generate ATP through simultaneous anaerobic glucose and amino acid fermentation even in the presence of oxygen. Our results support the Warburg cancer theory and suggest that besides glucose fermentation in the cytoplasm, glutamine fermentation in the mitochondria might also serve as an alternative compensatory energy source to OxPhos deficiency. Supported by Boston College Res. Fund. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 985. doi:10.1158/1538-7445.AM2011-985