Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth

Daniela Gaglio, Christian M. Metallo, Paulo A. Gameiro, Karsten Hiller, Lara Sala Danna, Chiara Balestrieri, Lilia Alberghina, Gregory Stephanopoulos, Ferdinando Chiaradonna

Research output: Contribution to journalArticlepeer-review


Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed 13 C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of 15 N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells. [-] [-].

Original languageEnglish
Article number523
JournalMolecular Systems Biology
Publication statusPublished - 2011


  • cancer
  • metabolic flux analysis
  • metabolism
  • Ras
  • transcriptional analysis

ASJC Scopus subject areas

  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Computational Theory and Mathematics
  • Information Systems
  • Applied Mathematics


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