Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM).
BACKGROUND
Metabolic 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.


RESULTS
Many 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.


CONCLUSIONS
PC 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.
Fan
Teresa W M
TW
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, USA. twmfan@gmail.com
Lane
Andrew N
AN
Higashi
Richard M
RM
Farag
Mohamed A
MA
Gao
Hong
H
Bousamra
Michael
M
Miller
Donald M
DM
D000368:Aged; D002247:Carbon Isotopes; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling / Q000379:methods*; D019344:Lactic Acid / Q000378:metabolism; D016014:Linear Models; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D019906:Nuclear Magnetic Resonance, Biomolecular; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011766:Pyruvate Carboxylase / Q000378:metabolism
D002247:Carbon Isotopes; D019344:Lactic Acid; D011766:Pyruvate Carboxylase; D005947:Glucose