Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK et al.. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105: 18782-18787

Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2008; 105(48):18782-7. DOI: 10.1073/pnas.0810199105
Source: PubMed


Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report 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. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.

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Available from: Ralph J Deberardinis, Oct 07, 2015
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    • "hypoxia), a-ketoglutarate produced from glutamate can undergo reductive carboxylation to generate citrate, oxaloacetate and acetyl-CoA to support anabolic processes anaerobically (Fig 1) (Mullen et al, 2012). As expected, GLS was found to be overexpressed in a number of tumors, and its inhibition delays tumor growth (Lobo et al, 2000; Wise et al, 2008). "
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    ABSTRACT: Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigenicity and malignancy. In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one of the hallmarks of cancer. Deciphering the full scope and functional implications of the dysregulated metabolism in cancer requires both the advancement of a variety of omics measurements and the advancement of computational approaches for the analysis and contextualization of the accumulated data. Encouragingly, while the metabolic network is highly interconnected and complex, it is at the same time probably the best characterized cellular network. Following, this review discusses the challenges that genome-scale modeling of cancer metabolism has been facing. We survey several recent studies demonstrating the first strides that have been done, testifying to the value of this approach in portraying a network-level view of the cancer metabolism and in identifying novel drug targets and biomarkers. Finally, we outline a few new steps that may further advance this field. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Molecular Systems Biology 06/2015; 11(6):817. DOI:10.15252/msb.20145307 · 10.87 Impact Factor
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    • "The metabolic changes in cancer cells are brought about through oncogene activation and loss of tumor suppressors. The MYC oncoprotein increases expression of the enzyme glutaminase synthase 1 [144] [145], which deaminates glutamine to produce glutamate. This reaction is the first step in glutaminolysis and it also supplies glutamate for the synthesis of glutathione. "
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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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    • "and, via conversion to a-ketoglutarate, as an ATP source through the tricarboxylic acid cycle (TCA) cycle and oxidative phosphorylation . L-Gln metabolism is transcriptionally regulated by Myc (Gao et al., 2009; Wise et al., 2008), which also suppresses microRNA-23a/b to enhance expression of the glutaminase 1 (GLS1) (Liu et al., 2012). Among Gln transporters, SLC1A5 is highly expressed in BCa cells and is also implicated in regulation of essential amino acid influx, mammalian target of rapamycin (mTOR) activation (Nicklin et al., 2009), and L-Gln-dependent tumor cell growth (Hassanein et al., 2013). "
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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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