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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LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma
Ana Galan-Cobo,Piyada Sitthideatphaiboon,Xiao Qu,Alissa Poteete,Marlese Pisegna,Pan Tong,Pei Hsuan Chen,Lindsey K. Boroughs,Mirna Rodriguez,Winter Zhang,Francesco Parlati,Jing Wang,Varsha Gandhi,Ferdinandos Skoulidis,Ralph J. DeBerardinis,John D. Minna,John V. Heymach +16 more
TL;DR: Findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma.
Metabolic Regulation of Protein N-Alpha-Acetylation by Bcl-xL Promotes Cell Survival
Caroline H. Yi,Heling Pan,Jan Seebacher,Il Ho Jang,Sven G. Hyberts,Gregory J. Heffron,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Renliang Yang,Fupeng Li,Jason W. Locasale,Hadar Sharfi,Bo Zhai,Ricard A. Rodriguez-Mias,Harry Luithardt,Lewis C. Cantley,Lewis C. Cantley,George Q. Daley,John M. Asara,John M. Asara,Steven P. Gygi,Gerhard Wagner,Chuan-Fa Liu,Junying Yuan +24 more
TL;DR: In this paper, a biochemical assay was proposed to detect the acetylation status of proteins and demonstrate that protein N-alpha-acetylation is regulated by the availability of acetyl-CoA.
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Tumor cell metabolism: an integral view.
Susana Romero-Garcia,Jose Sullivan Lopez-Gonzalez,José Luis Báez-Viveros,Dolores Aguilar-Cazares,Heriberto Prado-Garcia +4 more
TL;DR: An integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements.
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Viral effects on metabolism: changes in glucose and glutamine utilization during human cytomegalovirus infection
TL;DR: Recognition of the effects of HCMV, and other viruses, on host cell metabolism will provide new understanding of viral pathogenesis and novel avenues for antiviral therapy.
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Immunity, Hypoxia, and Metabolism-the Ménage à Trois of Cancer: Implications for Immunotherapy.
Carla Riera-Domingo,Carla Riera-Domingo,Annette Audigé,Sara Granja,Wan-Chen Cheng,Wan-Chen Cheng,Ping-Chih Ho,Ping-Chih Ho,Fátima Baltazar,Christian Stockmann,Massimiliano Mazzone,Massimiliano Mazzone +11 more
TL;DR: This review will discuss how a metabolic characterization of the TME can identify novel targets and signatures that could be exploited in combination with standard immunotherapies and can help to predict the benefit of new and traditional immunotherapeutic drugs.
References
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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.
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