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PMID: 23473032 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell metabolism ·Vol. 17 ·No. 3 ·2013-03-05 ·Pages 372-85

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

Abstract

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.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/metabolism Carbon Isotopes/metabolism Carboxylic Acids/metabolism Carcinoma, Renal Cell/metabolism Cell Line, Tumor Citrates/metabolism Extracellular Fluid/metabolism Gas Chromatography-Mass Spectrometry Glutamine/deficiency Humans Magnetic Resonance Spectroscopy Mice Models, Biological Oxidation-Reduction Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemicals
Basic Helix-Loop-Helix Transcription Factors Carbon Isotopes Carboxylic Acids Citrates Glutamine endothelial PAS domain-containing protein 1 Von Hippel-Lindau Tumor Suppressor Protein VHL protein, human
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Gameiro Paulo A
Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Yang Juanjuan
Metelo Ana M
Pérez-Carro Rocio
Baker Rania
Wang Zongwei
Arreola Alexandra
Rathmell W Kimryn
Olumi Aria
López-Larrubia Pilar
Stephanopoulos Gregory
Iliopoulos Othon
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Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1932-7420
DOI
10.1016/j.cmet.2013.02.002
Published
2013-03-05
Pages
372-85
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC4003458
Subset
IM
Grants
NCI NIH HHS · P30 CA016086 · United States
NCI NIH HHS · R01 CA122591 · United States
NCI NIH HHS · R01 CA160458 · United States
NIDDK NIH HHS · R01 DK075850 · United States
Corrections
CommentIn
PMID: 23584335
External Links
PubMed source DOI: 10.1016/j.cmet.2013.02.002 PMC Full Text View journal details
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