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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    • "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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    • "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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    • "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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