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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AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress
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Targeting Glutamine Metabolism for Cancer Treatment
Yeon-Kyung Choi,Keun-Gyu Park +1 more
TL;DR: An overview of the role of glutamine metabolism in cancer cell survival and growth is provided and the potential therapeutic approaches of targeting glutamines metabolism for the treatment of numerous types of cancer are summarized.
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Oxidative phosphorylation in cancer cells.
TL;DR: The peculiarity of tumour mitochondrial bioenergetics and the mode it is linked to the cell metabolism is reviewed, providing a short overview of the evidence accumulated so far, but highlighting the more recent advances.
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Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth.
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TL;DR: A role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors is defined.
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The Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase
Marco Sciacovelli,Giulia Guzzo,Virginia Morello,Christian Frezza,Liang Zheng,Nazarena Nannini,Fiorella Calabrese,Gabriella Laudiero,Franca Esposito,Matteo Landriscina,Paola Defilippi,Paolo Bernardi,Andrea Rasola +12 more
TL;DR: These findings provide a mechanistic clue to explain the switch to aerobic glycolysis of tumors and identify TRAP1 as a promising antineoplastic target.
References
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