Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells.

Abstract

Metabolic reprogramming is critical to oncogenesis, but the emergence and function of this profound reorganization remain poorly understood. Here we find that cooperating oncogenic mutations drive large-scale metabolic reprogramming, which is both intrinsic to cancer cells and obligatory for the transition to malignancy. This involves synergistic regulation of several genes encoding metabolic enzymes, including the lactate dehydrogenases LDHA and LDHB and mitochondrial glutamic pyruvate transaminase 2 (GPT2). Notably, GPT2 engages activated glycolysis to drive the utilization of glutamine as a carbon source for TCA cycle anaplerosis in colon cancer cells. Our data indicate that the Warburg effect supports oncogenesis via GPT2-mediated coupling of pyruvate production to glutamine catabolism. Although critical to the cancer phenotype, GPT2 activity is dispensable in cells that are not fully transformed, thus pinpointing a metabolic vulnerability specifically associated with cancer cell progression to malignancy.

• Authors: Bradley Smith, Xenia L Schafer, Aslihan Ambeskovic, Cody M Spencer, Hartmut Land, Joshua Munger
• Journal: Cell reports (Cell Rep) Vol. 17 Issue 3 Pg. 821-836 (10 11 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27732857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Isoenzymes
• Tumor Suppressor Protein p53
• Glutamine
• L-Lactate Dehydrogenase
• GPT2 protein, human
• Transaminases

Topics

• Carcinogenesis (metabolism, pathology)
• Cell Hypoxia
• Cell Line, Tumor
• Cell Proliferation
• Citric Acid Cycle
• Genes, ras
• Glutamine (metabolism)
• Glycolysis
• Humans
• Isoenzymes (metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Mutation (genetics)
• Neoplasms (metabolism, pathology)
• Phenotype
• Transaminases (metabolism)
• Tumor Suppressor Protein p53 (metabolism)