Abstract
BackgroundMetabolic perturbations arising from malignant transformation have not been systematically characterized in human lung cancers in situ. Stable isotope resolved metabolomic analysis (SIRM) enables functional analysis of gene dysregulations in lung cancer. To this purpose, metabolic changes were investigated by infusing uniformly labeled 13C-glucose into human lung cancer patients, followed by resection and processing of paired non-cancerous lung and non small cell carcinoma tissues. NMR and GC-MS were used for 13C-isotopomer-based metabolomic analysis of the extracts of tissues and blood plasma.ResultsMany primary metabolites were consistently found at higher levels in lung cancer tissues than their surrounding non-cancerous tissues. 13C-enrichment in lactate, Ala, succinate, Glu, Asp, and citrate was also higher in the tumors, suggesting more active glycolysis and Krebs cycle in the tumor tissues. Particularly notable were the enhanced production of the Asp isotopomer with three 13C-labeled carbons and the buildup of 13C-2,3-Glu isotopomer in lung tumor tissues. This is consistent with the transformations of glucose into Asp or Glu via glycolysis, anaplerotic pyruvate carboxylation (PC), and the Krebs cycle. PC activation in tumor tissues was also shown by an increased level of pyruvate carboxylase mRNA and protein.ConclusionPC activation – revealed here for the first time in human subjects – may be important for replenishing the Krebs cycle intermediates which can be diverted to lipid, protein, and nucleic acid biosynthesis to fulfill the high anabolic demands for growth in lung tumor tissues. We hypothesize that this is an important event in non-small cell lung cancer and possibly in other tumor development.
Highlights
Metabolic perturbations arising from malignant transformation have not been systematically characterized in human lung cancers in situ
Activation of glycolysis in human lung cancers and cancer cells was inferred from an up-regulation of glycolysis-related enzymes such as hexokinase II (HK II), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the bifunctional regulatory enzyme phosphofructokinase 2 (PFK-2) [2,3,4,5,6,7]
GC-mass spectrometry (MS) analysis revealed a significant presence of mass isotopomers of lactate with one or two 13C labels for patients #8–10, which is consistent with an active Cori cycle [9]
Summary
Metabolic perturbations arising from malignant transformation have not been systematically characterized in human lung cancers in situ. Activation of glycolysis in human lung cancers and cancer cells was inferred from an up-regulation of glycolysis-related enzymes such as hexokinase II (HK II), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the bifunctional regulatory enzyme phosphofructokinase 2 (PFK-2) [2,3,4,5,6,7] These enzyme expression changes associated with glucose oxidation are accompanied by an up-regulation of glucose transporters (e.g. GLUT 1) in non-small-cell lung cancers (NSCLC) [8]. Several of the Krebs cycle metabolites, such as citrate, oxaloacetate/aspartate, and α-ketoglutarate/glutamate are respective precursors for the biosynthesis of fatty acids, nucleic acids and proteins [9], all of which are required for growth As some of these metabolites (e.g. oxaloacetate and α-ketoglutarate) are kept low in their cellular concentration, they will have to be replenished via anaplerosis to sustain both Krebs cycle and biosynthetic activities. The relative importance of these two pathways appears to be tissue specific [10,12,13]
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