Cell metabolism and c-Myc-induced growth, proliferation and neoplasia.
EMSL Project ID
21592
Abstract
Chemical and radiological damage to cells can result in inactivation of tumor suppressors or activation of oncogenes, increasing the risk of cancer. The c-Myc oncogene (Myc) is deregulated in over 50% of human cancers and two decades of molecular research on this transcription factor has established Myc's role in the regulation of gene expression required for cancer cell proliferation and growth. While many Myc target genes have been identified, it is still unclear how the products of these genes cooperate in Myc-induced tumorogenesis. Metabolic pathways are prime examples of cooperative networks and metabolic genes are regulated by Myc. However, the functional significance of this regulation to Myc-induced neoplasia remains to be elucidated. Myc's role in glycolysis is well established and our demonstration that Myc induces genes for mitochondrial proteins suggests regulation of mitochondrial function. Because these two pathways are essential for energy generation, we hypothesized that Myc coordinates interacting metabolic pathways to provide the metabolites and energy required for proliferation, growth and neoplasia. In our funded NIH grant we proposed the use of Myc wild-type and null isogenic cell lines and mouse models with tissue specific, inducible Myc expression to address this hypothesis. Briefly these models are being used to address the following specific aims; Specific aim 1. Determine the metabolic changes that accompany Myc-induced cell proliferation and growth. Specific aim 2. Determine the metabolic changes arising during Myc-induced neoplasia in a mouse model of reversible pancreatic neoplasia. These studies come under the EMSL science theme of biological interactions, as this research would advance our scientific understanding of how oncogenes regulate metabolic networks. Our preliminary results, using a panel of isogenic rat fibroblast cell lines with differential Myc expression, demonstrate that coupling of oxidative phosphorylation and glycolysis facilitates rapid, Myc-induced cell cycle entry. To unequivocally prove this linkage we are requesting access to EMSL facilities to perform 13C isotopomer analysis of cells grown in U-13C6 glucose during cell cycle entry, as the cryogenic probes available at EMSL would provide the most comprehensive data acquisition. These experiments will define how the presence of Myc regulates flux through metabolic networks to induce cell proliferation. Our NIH grant also proposed the use of unique tissue specific, inducible mouse models to evaluate the metabolic events underlying Myc-induced growth in the heart and Myc-induced neoplasia in the pancreas. This latter model provides a powerful tool to address critical metabolic events required for neoplasia, as pancreatic tumors regress in the absence of Myc. We anticipate breeding mice for these studies within the next six months and request access to EMSL facilities to begin NMR analysis. When completed these studies will provide distinct profiles of carbon metabolism linked to Myc induced neoplasia and growth. Recent research has revealed that targeting metabolic pathways may provide unique approaches to selectively kill cancer cells. Data generated from our 13C isotopomer and related metabolic studies will increase our knowledge of Myc's regulation of metabolic networks and further biomarker and drug discovery efforts for cancer diagnostics and treatment.
Project Details
Project type
Capability Research
Start Date
2007-01-20
End Date
2007-07-18
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry
F Morrish, N Isern, M Sadilek, M Jeffrey and DM Hockenbery
Oncogene (2009) 1–7 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09