title: Hypoxia promotes mitochondrial glutamine metabolism through HIF1α-GDH pathway in human lung cancer cells.
abstract: 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.
authors.affiliation: Department of Pulmonary Medicine, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, Anhui, PR China. Electronic address: jiangid4@163.com.
authors.forename: Zi-Feng
authors.initials: ZF
authors.lastname: Jiang
authors.affiliation: Department of Respiratory Medicine, Anhui Chest Hospital, Jixi Road 397, Hefei 230022, Anhui, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, PR China.
authors.forename: Jian-Lin
authors.initials: JL
authors.lastname: Xu
authors.affiliation: Department of Pulmonary Medicine, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, Anhui, PR China.
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Ning
mesh_terms: D000072283:A549 Cells; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D005969:Glutamate Dehydrogenase; D005973:Glutamine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human
keywords: Cisplatin; GDH; Glutamine; HIF; Hypoxia; Lung cancer