1. ¹Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
2. ²WR Wiley Environmental Molecular Sciences Laboratory, High Field NMR Facility, Pacific Northwest National Laboratory, Richland, WA, USA
3. ³Department of Chemistry, University of Washington, Seattle, WA, USA
4. ⁴Advanced Imaging Research Center, University of Texas Southwestern, Dallas, TX, USA

Correspondence: Dr DM Hockenbery, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D2-190, Seattle, WA 98109, USA. E-mail: dhockenb@fhcrc.org

Received 9 November 2008; Revised 1 February 2009; Accepted 18 February 2009; Published online 18 May 2009.

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.