Abstract #SY18-2: The role of myc in cancer metabolism in tumorigenesis

The MYC oncogene, which encodes c-Myc protein, is a master oncogenic transcription factor that contributes to the development of a large number of human cancers. The primordial function of MYC involves the regulation of ribosomal biogenesis and nucleolar function; however, its role appears to expand during evolution to involve regulation of the cell cycle and cellular metabolism, in particular, energy metabolism. MYC\#8217;s stimulation of ribosomal biogenesis, nucleotide metabolism, and regulation of the cell cycle machinery requires concomitant assurance that adequate energy is garnered by MYC\#8217;s regulation of mitochondrial biogenesis, glycolytic, glutamine and fatty acid metabolic genes. In this regard, the normal function of MYC involves the induction and coordination of cell proliferation and cellular metabolism, such that MYC\#8217;s deregulated expression in cancers demands higher energy supply, whose deficiency could trigger apoptosis. Myc regulates transcription globally, highlighting a core set of genes that involves ribosomal biogenesis and characterizes a stem cell signature. In addition, Myc regulates glucose and glutamine metabolism, which are two essential energy producing pathways that are also involved in biosynthetic pathways. In a Myc-dependent lymphoma model, we observed tumor microenvironment heterogeneity such that hypoxic areas are exclusive of DNA synthesis. Myc-overexpressing tumor cells, hence, must adapt and survive the adverse tumor microenvironment. The hypoxia inducible factor 1, HIF-1, permits adaptation to the hypoxic microenvironment through activation of genes involved in neo-angiogenesis and anaerobic glycolysis, which are also stimulated by Myc. When MYC-dependent tumors grow, hypoxia elevates the levels of HIF, such that oncogenic MYC and HIF could collaborate to increase the cancer cell\#8217;s metabolic needs through increased uptake of glucose and its conversion to lactate. The dependent of Myc-mediated tumorigenesis on HIF-1 was documented by the ability of N-acetylcysteine or Vitamin C to reactivate prolyl hydroxylases and diminish HIF-1 levels, markedly inhibiting lymphomagenesis. Myc could independently stimulate glutaminolysis or the conversion of glutamine to lactate, providing an energy source complementary to glucose. In this regard, Myc directly transactivates glutamine transporter genes as well as stimulates mitochondrial glutaminase via suppression of microRNAs, which are decreased in prostate cancer as compared with normal prostate tissue. These findings suggest that the metabolic phenotypes of cancers could vary from those dependent primarily on glutaminolysis and oxidative phosphorylation to those that have acquired the Warburg effect through activation of glycolysis. Hence, therapeutic targeting of cancer metabolism will require a better understanding of the genetic basic of altered tumor metabolism and metabolic profiling of specific cancer types.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY18-2.