Hypoxia promotes mitochondrial glutamine metabolism through HIF1α-GDH pathway in human lung cancer cells.

Drug-resistance is common in human lung cancer therapy. Hypoxia remarkably contributes to drug-resistance in lung cancer but the underlying mechanism remains elusive. Here we demonstrate that hypoxia-induced glutamine metabolism is involved in drug resistance in lung cancer cells. Hypoxia increases glutamine up-take, glutamate to α-ketoglutarate flux and the generation of ATP in lung cancer cells by up-regulating the expression of glutamate dehydrogenase (GDH). Hypoxia-induced expression of GDH relies on the up-regulation of HIF1α but not HIF2α. HIF1α binds the promoter of GDH and promotes the transcription of GDH gene in lung cancer cells. Finally, we show that GDH represses cisplatin-induced cell apoptosis and repression of colony formation, indicating that GDH contributes to drug-resistance in lung cancer cells. In conclusion, HIF1α-GDH pathway regulates glutamine metabolism and ATP production upon hypoxia stress and contributes to drug-resistance in human lung cancer cells.