Title: Differential metabolic flux distributions in NIH 3T3 mouse fibroblats with K-ras codon-specific mutations
Authors: Pedro de Atauri, Pedro Vizan, Adrian Benito, Miriam Zanuy, Vitaly Selivanov, Silvia Marin, and Marta Cascante
Abstract:Using transfected NIH 3T3 fibroblasts with a mutated K-ras minigene either at codon 12 (K12) or at codon 13 (K13), the flux distributions are determined in these two transfectant cell lines integrating isotopomer distribution on metabolic products synthesized from [1,2-13C2]-glucose with software tools that can analyze the isotopomer accumulation in metabolites. K-ras specific point mutations induce tumors with distinct survival strategies. 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. We show that codon 12 mutant K-ras (K12) transformed cells route more glucose to anaerobic glycolysis than in K13 transfectants. On the other hand, K13 cells display a completely different metabolic profile. K13 mutants route more glucose to the use of the nonoxidative pentose phosphate pathway and Krebs cycle than in K12 transfectants. The increased use of anabolic pathways occurs to the detriment of anaerobic glycolysis. 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 (K13).
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