Glutamine: fructose-6-phosphate aminotransferase 2 (GFPT2) is a novel NF-kB target that links cancer metabolism with metastatic phenotypes in non-small cell lung cancer

Lung cancer is one of the most prevalent cancer types and the leading cause of cancer related mortality in the world. Non-small cell lung cancer (NSCLC) constitutes the majority of lung cancers with the five-year survival rate at 17%. Poor survival rates are due to late-stage diagnosis and limited response to standard of care cisplatin-based chemotherapy. Recent efforts in targeted therapy in lung cancer yielded limited success due to the activation of compensatory survival mechanisms and acquisition of drug resistance. Metastasis in NSCLC is driven by the trans-differentiation process called epithelial to mesenchymal transition (EMT) that promotes migratory and invasive phenotypes in cancer cells. EMT is induced by cytokines secreted by cells present in tumor microenvironment. The Mayo laboratory has shown that transforming growth factor beta (TGFb) and tumor necrosis factor (TNF) cooperate to induce EMT in NSCLC and that activation of the nuclear factor kappa B (NF-kB) pathway is essential for the transition. Cancer cells show elevated uptake and utilization of glucose and glutamine via aerobic glycolysis (Warburg effect) and anaplerotic TCA cycle respectively. Glucose and glutamine are both required for the synthesis of UDP-N-acetylglucosamine (UDP-GlcNAc) in the hexosamine biosynthesis pathway (HBP). UDP-GlcNAc is a precursor molecule for multiple processes including protein glycosylation, generation of glycosaminoglycans and O-GlcNAcylation of nucleocytoplasmic proteins. Aberrant elevation of glycans has been implicated in cancer progression, survival and metastasis. Glutamine: fructose-6-phosphate (GFPT) is a first and rate-limiting enzyme in HBP. Here we show that neuronal-specific GFPT2 isoform is a novel NF-kB target, up-regulated during TNF/TGFb-induced EMT in NSCLC and in response to MEK inhibition in KRAS-mutant NSCLC. GFPT2 induction elevates protein O-GlcNAcylation in mesenchymal cells and is required for the migration and invasion of mesenchymal NSCLC. Consistent with these observations high GFPT2 expression correlates with poor clinical outcome of lung adenocarcinoma patients.