期刊
MOLECULAR SYSTEMS BIOLOGY
卷 9, 期 -, 页码 -出版社
WILEY
DOI: 10.1038/msb.2013.65
关键词
cancer bioenergetics; isotope tracing; metabolic flux analysis
资金
- NIH [P50 GM071508, 1RC1 CA147961-02, CA163591-01A1]
- Stand Up To Cancer
- HHMI international student research fellowship
- Hope Funds for Cancer Research [HFCR-11-03-01]
- Israel Science Foundation
Mammalian cells can generate ATP via glycolysis or mitochondrial respiration. Oncogene activation and hypoxia promote glycolysis and lactate secretion. The significance of these metabolic changes to ATP production remains however ill defined. Here, we integrate LC-MS-based isotope tracer studies with oxygen uptake measurements in a quantitative redox-balanced metabolic flux model of mammalian cellular metabolism. We then apply this approach to assess the impact of Ras and Akt activation and hypoxia on energy metabolism. Both oncogene activation and hypoxia induce roughly a twofold increase in glycolytic flux. Ras activation and hypoxia also strongly decrease glucose oxidation. Oxidative phosphorylation, powered substantially by glutamine-driven TCA turning, however, persists and accounts for the majority of ATP production. Consistent with this, in all cases, pharmacological inhibition of oxidative phosphorylation markedly reduces energy charge, and glutamine but not glucose removal markedly lowers oxygen uptake. Thus, glutamine-driven oxidative phosphorylation is a major means of ATP production even in hypoxic cancer cells.
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