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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Beta-hydroxybutyrate (3-OHB) can influence the energetic phenotype of breast cancer cells, but does not impact their proliferation and the response to chemotherapy or radiation
Catharina Bartmann,Sudha Janaki Raman,Jessica Flöter,Almut Schulze,Katrin Bahlke,Jana Willingstorfer,Maria Strunz,Achim Wöckel,Rainer J. Klement,Michaela Kapp,Cholpon S. Djuzenova,Christoph Otto,Ulrike Kämmerer +12 more
TL;DR: It is found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines, but there is no evidence that 3- OHB generally influences the biology of breast cancer cells in vitro.
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Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst
Inge Grondman,Rob J.W. Arts,Rebecca M. Koch,Guus P. Leijte,Jelle Gerretsen,Niklas Bruse,Rosalie W. M. Kempkes,Rob ter Horst,Matthijs Kox,Peter Pickkers,Mihai G. Netea,Mihai G. Netea,Mark S. Gresnigt,Mark S. Gresnigt +13 more
TL;DR: It is demonstrated that immunotolerant monocytes are characterized by a loss of metabolic plasticity and these metabolic defects impact antimicrobial monocyte immune functions, and support that the changed cellular metabolism of immunot tolerant monocytes might reveal novel therapeutic targets to reverse sepsis‐induced immunoparalysis.
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Glutathione and its precursors in cancer.
Gloria Asantewaa,Isaac S. Harris +1 more
TL;DR: In this article, the authors focus on GSH, the most abundant antioxidant in the cell, and its precursor amino acids (cysteine, glutamate, and glycine) and its ability to promote different stages of tumorigenesis.
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Provocative Question: Should Ketogenic Metabolic Therapy Become the Standard of Care for Glioblastoma?
Thomas N. Seyfried,Laura M. Shelton,Gabriel Arismendi-Morillo,Miriam Kalamian,Ahmed M. A. Elsakka,Joseph C. Maroon,Purna Mukherjee +6 more
TL;DR: Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability while elevating ketone bodies that are neuroprotective and non-fermentable, thus improving progression free and overall survival for patients with GBM.
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Oncogene Activation Induces Metabolic Transformation Resulting in Insulin-Independence in Human Breast Cancer Cells
TL;DR: This study investigated the mechanism by which oncogene over expression transforms MCF10A cells to an insulin-independent phenotype, and identified genes specifically regulated by the HER2 oncogen, including VAMP8 and PHGDH, which have known functions in glucose uptake and processing of glycolytic intermediates, respectively.
References
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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.