DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CBBeyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104: 19345-19350

Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Room 450, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2008; 104(49):19345-50. DOI: 10.1073/pnas.0709747104
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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.

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    • "Therefore, ACL represents a key enzyme linking glucose metabolism to lipid synthesis, fundamental for tumor cell growth [38]. Moreover, proliferating tumor cells exhibit elevated glutamine consumption, so as to provide NADPH and anaplerotic oxaloacetate to maintain citrate production in the first step of the TCA cycle needed for fatty acid synthesis [39]. "
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    ABSTRACT: Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). We analyzed the key metabolic abnormalities underlying RCC carcinogenesis, highlighting those altered pathways that may represent potential targets for the development of more effective therapeutic strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cancer Treatment Reviews 07/2015; DOI:10.1016/j.ctrv.2015.07.002 · 7.59 Impact Factor
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    • "© the Biochemical Society. [141] [142]. The latter process is called glutaminolysis or anaplerosis . "
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    ABSTRACT: In the absence of oxygen human life is measured in minutes. In the presence of oxygen, normal metabolism generates reactive species (ROS) that have the potential to cause cell injury contributing to human aging and disease. Between these extremes, organisms have developed means for sensing oxygen and ROS and regulating their cellular processes in response. Redox signaling contributes to the control of cell proliferation and death. Aberrant redox signaling underlies many human diseases. The attributes acquired by altered redox homeostasis in cancer cells illustrate this particularly well. This teaching review and the accompanying illustrations provide an introduction to redox biology and signaling aimed at instructors of graduate and medical students. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    04/2015; 87. DOI:10.1016/j.redox.2015.04.002
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    • "Moreover, SLC1A5 inhibition in hepatoma and acute myeloid leukemia cells attenuates mTORC1 signaling, resulting in growth repression and apoptosis (Fuchs et al., 2007; Willems et al., 2013), suggesting a role in cellular transformation (Witte et al., 2002). Mechanisms underlying control of SLC1A5-mediated L-Gln uptake in tumor cells and implications for the tumor cell response to therapy are largely unknown (DeBerardinis et al., 2007). The glutamine transporter SLC38A2 is more ubiquitously expressed, although elevated SLC38A2 expression has been reported in prostate tumors (Okudaira et al., 2011). "
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    ABSTRACT: Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 03/2015; 27(3):354-69. DOI:10.1016/j.ccell.2015.02.006 · 23.52 Impact Factor
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