NOX4 supports glycolysis and promotes glutamine metabolism in non-small cell lung cancer cells

Our previous studies have confirmed that NADPH oxidase 4 (NOX4) is abundantly expressed in non-small cell lung cancer (NSCLC) and contributes to cancer progression. Nevertheless, the comprehensive mechanisms for NOX4-mediated malignant progression and oxidative resistance of cancer cells remain largely unknown. This study found that NOX4 directed glucose metabolism not only to the glycolysis but also to pentose phosphate pathway (PPP) pathway for production of NADPH in NSCLC cell lines. Besides, we also found that NOX4 promoted glutaminolysis into total GSH synthesis. Specifically, the data showed that ectopic NOX4 expression did not induce apoptosis of NSCLC cells; however, inhibition of GSH production resulted in obvious apoptotic death of NOX4-overexpressed NSCLC cells. Furthermore, we demonstrated that NOX4-induced glycolysis probably via ROS/PI3K/Akt signaling-dependent c-Myc upregulation. The selective NOX4 inhibitor, GKT137831, significantly inhibited glucose and glutamine metabolic phenotypes both in vitro and in vivo, and itself or combination with 2-DG, a synthetic glycolytic inhibitor, suppressed cancer cell growth both in vivo and in vitro. Elimination of NOX4-derived H2O2 effectively reversed NOX4 overexpression-mediated metabolic effects in NSCLC cells. NOX4 levels were significantly correlated with increased glucose and glutamine metabolism-related genes, as well as Akt phosphorylation and c-Myc expression in primary NSCLC specimens. In conclusion, these results reveal that NOX4 promotes glycolysis, contributing to NSCLC growth, and supports glutaminolysis for oxidative resistance. Therefore, NOX4 may be a promising target to reverse malignant progression of NSCLC.