title: 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.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Xenia L
authors.initials: XL
authors.lastname: Schafer
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Aslihan
authors.initials: A
authors.lastname: Ambeskovic
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Cody M
authors.initials: CM
authors.lastname: Spencer
authors.affiliation: 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.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Land
authors.affiliation: 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.
authors.forename: Joshua
authors.initials: J
authors.lastname: Munger
mesh_terms: D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002952:Citric Acid Cycle; D011905:Genes, ras; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D000637:Transaminases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; D007770:L-Lactate Dehydrogenase; C000608785:GPT2 protein, human; D000637:Transaminases
keywords: GPT2; LDHA; LDHB; TCA cycle; Warburg effect; anaplerosis; cancer metabolism; glycolysis; lactate dehydrogenase; oncogenes