Beyond aerobic glycolysis : Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis
Ralph J. DeBerardinis,Anthony A. Mancuso,Evgueni Daikhin,Ilana Nissim,Marc Yudkoff,Suzanne Wehrli,Craig B. Thompson +6 more
TLDR
Transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools, and glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.Abstract:
Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.read more
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Pyruvate carboxylase is required for glutamine-independent growth of tumor cells
Tzuling Cheng,Jessica Sudderth,Chendong Yang,Andrew R. Mullen,Eunsook S. Jin,José M. Matés,Ralph J. DeBerardinis +6 more
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Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation
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References
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Journal ArticleDOI
Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells.
TL;DR: Observations suggest that glutamine provides energy by aerobic oxidation from citric acid cycle metabolism, provides more than half of the cell energy when high concentrations of glucose are present, and greater than 98% when fructose or galactose is the carbohydrate.
Journal ArticleDOI
ATP citrate lyase inhibition can suppress tumor cell growth
Georgia Hatzivassiliou,Fangping Zhao,Daniel E. Bauer,Charalambos Andreadis,Shaw Antony N,Dashyant Dhanak,Sunil R. Hingorani,David A. Tuveson,Craig B. Thompson +8 more
TL;DR: ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor cells displaying aerobic glycolysis, and these treatments also reduce in vivo tumor growth and induce differentiation.