Abstract
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-13C] glucose in serum-stimulated myc−/− and myc+/+ fibroblasts by 13C isotopomer NMR analysis. We demonstrate that endogenous c-myc increased 13C 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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Acknowledgements
We thank John Sedivy for cell lines. This work utilized the MMC database supported by NIH grants R21 DK070297 and P41 RR02301, the MDL database (www.mdl.imb.liu.se) and the Human Metabolome database (www.hmbd.ca). A portion of this research was performed at EMSL, a national scientific user facility sponsored by the Department of Energy's Office of Biological and Environmental Research at Pacific Northwest National Laboratory. This work was funded by RO1CA106650-02 (DH). Development of the program tcaCALC (University of Texas Southwestern Medical Center) was supported by H47669-16, a Department of Veterans Affairs Merit Review Award to CR Malloy, and RR02584.
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Morrish, F., Isern, N., Sadilek, M. et al. c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry. Oncogene 28, 2485–2491 (2009). https://doi.org/10.1038/onc.2009.112
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DOI: https://doi.org/10.1038/onc.2009.112
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