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

Teresa W.M. Fan, Andrew N. Lane, Richard M. Higashi, Mohamed A. Farag, Hong Gao, Michael Bousamra, Donald M. Miller

Research output: Contribution to journalArticlepeer-review

352 Scopus citations

Abstract

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. Conclusion: 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.

Original languageEnglish
Article number41
JournalMolecular Cancer
Volume8
DOIs
StatePublished - Jun 26 2009

Bibliographical note

Funding Information:
This work was supported in part by the National Cancer Institute grant # 1R01CA101199-01 and 1R01CA118434-01A2, NIH Grant Number RR018733 from the National Center for Research Resources, National Science Foundation EPSCoR grant # EPS-0132295 and EPS-0447479, Kentucky Lung Cancer Research Program, Kentucky Challenge for Excellence, and the Brown Foundation. We thank Ms. Vennila Arumugam for sample processing and extraction, Dr. Zhengzhi Xie for supplementary GC-MS data analysis, and Ms. Jamie Day for preclinical support

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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