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

K-ras Codon-Specific Mutations Produce Distinctive Metabolic Phenotypes in Human Fibroblasts 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- 13 C 2 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Research American Association of Cancer Research

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

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

Cancer Research , Volume 65 (13): 5512 – Jul 1, 2005

Abstract

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- 13 C 2 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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References (18)

Publisher
American Association of Cancer Research
Copyright
Copyright © 2005 by the American Association for Cancer Research.
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-05-0074
pmid
15994921
Publisher site
See Article on Publisher Site

Abstract

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- 13 C 2 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.

Journal

Cancer ResearchAmerican Association of Cancer Research

Published: Jul 1, 2005

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