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Journal ArticleDOI

Beyond aerobic glycolysis : Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis

TL;DR: 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.
Citations
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Journal ArticleDOI
22 May 2009-Science
TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

12,380 citations

Journal ArticleDOI
TL;DR: Interest in the topic of tumour metabolism has waxed and waned over the past century, but it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
Abstract: Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

4,169 citations

Journal ArticleDOI
TL;DR: This Perspective has organized known cancer-associated metabolic changes into six hallmarks: deregulated uptake of glucose and amino acids, use of opportunistic modes of nutrient acquisition, useof glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, increased demand for nitrogen, alterations in metabolite-driven gene regulation, and metabolic interactions with the microenvironment.

3,565 citations


Cites background from "Beyond aerobic glycolysis : Transfo..."

  • ...Most proliferating cells depend on a continuous supply of glutamine to maintain the integrity of TCA cycle intermediates (DeBerardinis et al., 2007)....

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Journal ArticleDOI
TL;DR: This review examines the idea that several core fluxes, including aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis, form a stereotyped platform supporting proliferation of diverse cell types and regulates regulation of these fluxes by cellular mediators of signal transduction and gene expression.

3,526 citations


Cites background from "Beyond aerobic glycolysis : Transfo..."

  • ...Nuclear magnetic resonance (NMR) spectroscopy using 13C-labeled substrates has revealed the use of glutamine as the major anaplerotic precursor in proliferating glioma cells in both rats (Portais et al., 1996) and humans (DeBerardinis et al., 2007)....

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Journal ArticleDOI
TL;DR: It is argued that altered metabolism has attained the status of a core hallmark of cancer.

2,623 citations


Cites background from "Beyond aerobic glycolysis : Transfo..."

  • ...While the role of glutamine as a nitrogen donor is important for the proliferation of these cells, their viability depends on glutamine as a carbon source for mitochondrial metabolism (DeBerardinis et al., 2007; Fan et al., 2010; Gao et al., 2009; Wise et al., 2008; Yuneva et al., 2007)....

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  • ...While critical fluxes have been quantified in cultured cancer cells, and methods for these analyses continue to improve (DeBerardinis et al., 2007; Mancuso et al., 2004; Yuan et al., 2008), many obstacles remain, such as cellular compartmentalization and the reliance of most cell culture on…...

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References
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Journal ArticleDOI
Otto Warburg1
24 Feb 1956-Science

10,654 citations

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8,572 citations

Journal ArticleDOI
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2,524 citations

Journal ArticleDOI
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.

1,161 citations

Journal ArticleDOI
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.

901 citations