Preliminary Studies On The Founction And Molecular Mechanism Of Glutamine Metabolism In Non-small Cell Lung Cancer

Metabolic alteration is one of the hallmarks of cancer cells compared withnormal cells，many cancer cells take up substantial glucose and decompose themmainly through the process of aerobic glycolysis, these metabolic deregulation ofcancer cells was primitively described as the Warburg effect. Another critical aspectof the reprogramming of cancer cell metabolism reveals the addiction of cancer cellsto glutamine，cancer cells often show elevated glutamine utilization and highglutaminase activity. Glutamine metabolism provides cancer cells with buildingblocks for biosynthesis of macromolecules, besides this, it can also promote thedevelopment and progression of malignant tumors by integrating with signalingtransduction pathways.Due to the ageing of population, pollution of environment and enormoussmoking population, Lung cancer has exerted an serious influence on the health ofChinese population, with an increasing rate of morbidity and mortality. Of the twomain classifications of lung cancer, patients with small cell lung cancer respond wellto Chemotherapy and radiotherapy, whereas patients with non-small cell lung cancerare less responsive. To this end, we chose to investigate the importance of glutaminemetabolism in non-small cell lung cancer and try to reveal some possible molecularmechanisms. We found that non-small cell lung cancer cell lines show greatdependency on glutamine metabolism and high expression and activity ofglutaminase C(GAC). Treatment of non-small cell lung cancer cell lines with968, asmall molecule inhibitor of GAC, blocked its cell proliferation, cell viability, cellmigration and cell cycle. Inhibition of GAC with968or GAC specific siRNAinhibited the EGFR-RAF-MEK-ERK signaling pathway in non-small cell lung cancercell line. It is interesting to notice that inhibition of glutamine metabolism had little tono impact on HBE cells which are isolated from human normal bronchi, indicatingthe low dependence of normal cells on glutamine matabolism. Our results show thatGAC was the key enzyme in glutamine metabolism of non-small cell lung cancer,targeting GAC may represent a promising strategy for treatment of non-small cell lung cancer.