Drug-resistance is common in human lung cancer therapy. Hypoxia remarkably contributes to drugresistance 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 alpha-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 HIF1 alpha but not HIF2 alpha. HIF1 alpha 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, HIF1 alpha-GDH pathway regulates glutamine metabolism and ATP production upon hypoxia stress and contributes to drug-resistance in human lung cancer cells. (C) 2017 Elsevier Inc. All rights reserved.