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

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• 作者：Zi-Feng Jiang^a ; ^{jiangid4@163.com} ; ^{zfjiangahmu@163.com} ; Min Wang^b ; Jian-Lin Xu^c ; Ya-Jing Ning^a
• 关键词：Hypoxia ; Lung cancer ; GDH ; Glutamine ; HIF ; Cisplatin
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2017
• 出版时间：29 January 2017
• 年：2017
• 卷：483
• 期：1
• 页码：32-38
• 全文大小：1232 K
• 卷排序：483

文摘

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.