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Cell Rep. 2016 Oct 11;17(3):821-836. doi: 10.1016/j.celrep.2016.09.045.

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

Author information

1
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
2
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
3
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: land@urmc.rochester.edu.
4
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: josh.munger@rochester.edu.

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.

KEYWORDS:

GPT2; LDHA; LDHB; TCA cycle; Warburg effect; anaplerosis; cancer metabolism; glycolysis; lactate dehydrogenase; oncogenes

PMID:
27732857
PMCID:
PMC5108179
DOI:
10.1016/j.celrep.2016.09.045
[Indexed for MEDLINE]
Free PMC Article

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