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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ESPEN guidelines on nutrition in cancer patients
Jann Arends,Patrick Bachmann,Vickie E. Baracos,Nicole Barthelemy,Hartmut Bertz,Federico Bozzetti,Kenneth C. H. Fearon,Elisabeth Hütterer,Elizabeth Isenring,Stein Kaasa,Zeljko Krznaric,Barry Laird,Maria Larsson,Alessandro Laviano,Stefan Mühlebach,Maurizio Muscaritoli,Line Merethe Oldervoll,Paula Ravasco,Tora Skeidsvoll Solheim,Florian Strasser,Marian A. E. de van der Schueren,Jean-Charles Preiser +21 more
TL;DR: These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients.
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Mitochondria and cancer
TL;DR: Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment and activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.
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c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
Ping Gao,Irina Tchernyshyov,Tsung Cheng Chang,Yun-Sil Lee,Kayoko Kita,Takafumi Ochi,Karen I. Zeller,Angelo M. De Marzo,Jennifer E. Van Eyk,Joshua T. Mendell,Chi V. Dang +10 more
TL;DR: In this paper, the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.
Journal ArticleDOI
Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction
David R. Wise,Ralph J. DeBerardinis,Anthony A. Mancuso,Nabil Sayed,Xiao-yong Zhang,Harla K. Pfeiffer,Ilana Nissim,Evgueni Daikhin,Marc Yudkoff,Steven B. McMahon,Craig B. Thompson +10 more
TL;DR: It is reported that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis, resulting in the reprogramming of mitochondrial metabolism to depend on glutaminolysis to sustain cellular viability and TCA cycle anapleurosis.
Journal ArticleDOI
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
Ruoning Wang,Christopher P. Dillon,Lewis Zhichang Shi,Sandra Milasta,Robert Carter,David Finkelstein,Laura L. McCormick,Patrick Fitzgerald,Hongbo Chi,Joshua Munger,Douglas R. Green +10 more
TL;DR: Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines, which may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.
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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