C-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Oncogene (Impact Factor: 8.46). 06/2009; 28(27):2485-91. DOI: 10.1038/onc.2009.112
Source: PubMed


Cell proliferation requires the coordinated activity of cytosolic and mitochondrial metabolic pathways to provide ATP and building blocks for DNA, RNA and protein synthesis. Many metabolic pathway genes are targets of the c-myc oncogene and cell-cycle regulator. However, the contribution of c-Myc to the activation of cytosolic and mitochondrial metabolic networks during cell-cycle entry is unknown. Here, we report the metabolic fates of [U-(13)C] glucose in serum-stimulated myc(-/-) and myc(+/+) fibroblasts by (13)C isotopomer NMR analysis. We demonstrate that endogenous c-myc increased (13)C labeling of ribose sugars, purines and amino acids, indicating partitioning of glucose carbons into C1/folate and pentose phosphate pathways, and increased tricarboxylic acid cycle turnover at the expense of anaplerotic flux. Myc expression also increased global O-linked N-acetylglucosamine protein modification, and inhibition of hexosamine biosynthesis selectively reduced growth of Myc-expressing cells, suggesting its importance in Myc-induced proliferation. These data reveal a central organizing function for the Myc oncogene in the metabolism of cycling cells. The pervasive deregulation of this oncogene in human cancers may be explained by its function in directing metabolic networks required for cell proliferation.

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Available from: Nancy Isern
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    • "In summary, the MYC oncogene plays a central organizing function of proliferating cells metabolism, which explains the pervasive deregulation of c-Myc in human cancers [117]. Metabolic activity is a crucial determinant of a cell decision to proliferate or die. "
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    • "The metabolic reprogramming that results from Myc deregulation is exemplified by the “Warburg effect” whereby ATP originating from mitochondrial sources is largely supplanted by that derived from glycolysis, even in oxygen-rich environments [16]. Among the benefits thought to be afforded by the switch to this less efficient mode of energy generation is a redirecting of TCA intermediates away from ATP production and towards the synthesis of lipid, protein and nucleic acid precursors that serve the increased synthetic demands of the rapidly proliferating transformed cell [14], [16], [17], [18]. The resultant increases in mitochondrial biogenesis and metabolism that accompany this reprogramming are at least partly explained by the ability of Myc to regulate the expression of TFAM, a major determinant of mitochondrial DNA replication [12], as well as PGC-1α [19] and PGC-1β [15], which regulate mitochondrial mass and energy metabolism [20]. "
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