谷氨酰胺
脂肪生成
细胞内
体内
谷氨酰胺酶
ATP柠檬酸裂解酶
细胞培养
生物
柠檬酸合酶
内分泌学
化学
生物化学
癌症研究
内科学
新陈代谢
医学
酶
氨基酸
遗传学
生物技术
作者
Paulo A. Gameiro,Juanjuan Yang,Ana M. Metelo,Rocío Pérez-Carro,Rania Baker,Zongwei Wang,Alexandra Arreola,W. Kimryn Rathmell,Aria F. Olumi,Pilar López‐Larrubia,Gregory Stephanopoulos,Othon Iliopoulos
标识
DOI:10.1016/j.cmet.2013.02.002
摘要
Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduced intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis. Using [(1-13)C]glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice. Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts.
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