Oncogenic K-Ras Decouples Glucose and Glutamine Metabolism to Support Cancer Cell Growth

Overview

Journal Mol Syst Biol

Specialty Molecular Biology

Date 2011 Aug 18

PMID 21847114

Citations 284

Authors

Daniela Gaglio

Christian M Metallo

Paulo A Gameiro

Karsten Hiller

Lara Sala Danna

Chiara Balestrieri

Lilia Alberghina

Gregory Stephanopoulos

Ferdinando Chiaradonna

Affiliations

Soon will be listed here.

Abstract

Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed ¹³C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of ¹⁵N-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.

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