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K-ras Codon-Specific Mutations Produce Distinctive Metabolic Phenotypes in Human Fibroblasts

¹ Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona; ² Gastrointestinal Research Laboratory, Saint Pau Hospital; ³ Translational Research Laboratory, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain; and ⁴ SIDMAP, LLC and Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California

Requests for reprints: Marta Cascante, Department of Biochemistry and Molecular Biology, University of Barcelona, C/Martí i Franqués, 1, Barcelona 08028, Spain. Phone: 34-93-4021593; Fax: 34-39-4021219; E-mail: marta{at}bq.ub.es.

Among K-ras mutations, codon 12 mutations have been identified as those conferring a more aggressive phenotype. This aggressiveness is primarily associated with slow proliferation but greatly increased resistance to apoptosis. Using transfected NIH3T3 fibroblasts with a mutated K-ras minigene either at codon 12 (K12) or at codon 13 (K13), and taking advantage of [1,2-¹³C₂]glucose tracer labeling, we show that codon 12 mutant K-ras (K12)-transformed cells exhibit greatly increased glycolysis with only a slight increase in activity along pathways that produce nucleic acid and lipid synthesis precursors in the oxidative branch of the pentose phosphate pathway and via pyruvate dehydrogenase flux. K13 mutants display a modest increase in anaerobic glycolysis associated with a large increase in oxidative pentose phosphate pathway activity and pyruvate dehydrogenase flux. The distinctive differences in metabolic profiles of K12 and K13 codon mutated cells indicate that a strong correlation exists between the flow of glucose carbons towards either increased anaerobic glycolysis, and resistance to apoptosis (K12), or increased macromolecule synthesis, rapid proliferation, and increased sensitivity to apoptosis.

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