Metabolomics studies in lymph node aspirates demonstrate that lung tumor types can be diagnosed based on their metabolite profiles. Follow up studies show that 30% of lung tumors excrete high amounts of glutathione and from γ-glutamyl-amino acids. Subsequent validation experiments in lung tumor cell lines confirmed the increased excretion of glutathione and formation of γ-glutamyl-amino acids. GSH concentrations in lung tumors have been known to be as high as 10 mM, while formation of γ-glutamyl-amino acids has not been reported previously. About 50% of lung tumors express active γ-glutamyl transferase, an enzyme that hydrolyzes glutathione or transfers the γ-glutamyl from glutathione to free amino acids or dipeptides, if present at high concentrations. γ-glutamyl transferase is a key enzyme of the γ-glutamyl cycle, a biochemical pathway that had long been considered to be physiologically irrelevant because of the high km-values of the enzymes involved. However, the function and biological significance of high glutathione in lung tumors has been unanswered. We show herein that lung tumors make γ-glutamyl-amino acids, suggesting an active γ-glutamyl cycle in lung tumors. The observed extracellular glutathione and γ-glutamyl-glutamine led us to hypothesize that they participate in cell-cell interaction. Using a standard transformation assay, it is shown that γ-glutamyl-glutamine induces transformation in normal NIH-3T3 cells and small airway epithelial cells. In contrast, glutathione induces transformations only in GGT positive small airway epithelial cells. Based on these findings we conclude that glutathione is a universal amino acid checkpoint. When sufficient amino acids are available glutathione is metabolized to γ-glutamyl-glutamine, which subsequently triggers proliferation of tumor cells and transformation of normal epithelia cells.

Importance of the glutathione and its degradation by γ-glutamyl transferase in lung tumor development

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.