W. Rathmell
Last active: 8/8/2016

In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation.

Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R, Wang Z, Arreola A, Rathmell WK, Olumi A, López-Larrubia P, Stephanopoulos G, Iliopoulos O
Cell Metab. 2013 17 (3): 372-85

PMID: 23473032 · PMCID: PMC4003458 · DOI:10.1016/j.cmet.2013.02.002

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.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (16)

Animals Basic Helix-Loop-Helix Transcription Factors Carbon Isotopes Carboxylic Acids Carcinoma, Renal Cell Cell Line, Tumor Citrates Extracellular Fluid Gas Chromatography-Mass Spectrometry Glutamine Humans Magnetic Resonance Spectroscopy Mice Models, Biological Oxidation-Reduction Von Hippel-Lindau Tumor Suppressor Protein

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