Dependency of Non-Small Cell Lung Cancer Cells on Glutamine and Glucose Levels in the Presence of Metformin.

Metabolic shift is one of the hallmarks of cancer cells. Due to mutations in oncogenes such as Kirsten Rat Sarcoma Viral Oncogene (KRAS), cancer cells can adapt to stress-induced conditions. One of the adaptations that is commonly observed in non-small cell lung cancer (NSCLC) cells is glutaminolysis, where they exhibit high dependency on the presence of glutamine. Metformin is used for its anti-tumor effects, which inhibit mitochondrial complex I. This study aimed to investigate how glucose and glutamine availability affect the proliferation of three KRAS mutant NSCLC cells under metformin pressure. Using gene expression datasets, it was observed that glutamine was the second most affected metabolite upon metformin-treated A549 cells. Based on this, several 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were done by using high and low glucose conditions having different concentrations of glutamine at different time points. Moreover, metformin was added to the setup to observe the flexibility of the cancer cells in terms of metabolic switches. Addition of glutamine resulted in a decrease in metformin's antiproliferative effect especially in high glucose conditions at later time points. A significantly higher proliferation rate in low glucose conditions compared to high glucose conditions was observed, which is especially pronounced with the addition of glutamine. These observations were supported by the gene expression analysis of the GSE dataset, which revealed upregulation of apoptosis related genes and downregulation of proliferation-related genes in metformin-treated A549 cells. Taken together, the results highlight the importance of targeting different metabolites and metabolic pathways in cancer therapy.   Cite this article as: K.ker ŞC, Tura.lı İD. Dependency of non-small cell lung cancer (NSCLC) cells on glutamine and glucose levels in the presence of metformin. Eurasian J Med. 2026, 58(2), 1018, doi:10.5152/eurasianjmed.2026.251018.