In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation
Open accessAbstract
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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Malignant cells use glutaminolysis under hypoxic conditions.
“Numerous studies have reported that malignant cells use glutaminolysis under hypoxic conditions [82,83].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [83]
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References 47 · Cited by 325
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- Authors
- Gameiro, P. A., Yang, J., Metelo, A. M., Pérez-Carro, R., Baker, R., Wang, Z., Arreola, A., Rathmell, W. K., Olumi, A., López-Larrubia, P., Stephanopoulos, G., & Iliopoulos, O.
- Affiliations
- Massachusetts General Hospital (US)
- University of North Carolina at Chapel Hill (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Iliopoulos, Othon
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 17
- Issue
- 3
- Pages
- 372-385
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4003458
- OpenAlex
- W2120553786
- Cited by
- 325
- References
- 47
- Citations by year
- 2026: 23 · 2025: 17 · 2024: 17 · 2023: 27 · 2022: 24 · 2021: 24 · 2020: 26 · 2019: 28 · 2018: 16 · 2017: 31 · 2016: 22 · 2015: 33 · 2014: 27 · 2013: 9
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA160458, R01CA122591, P30CA016086)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075850)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- reductive carboxylation, hypoxia-inducible factor, VHL deficiency, citrate, glutamine deprivation, renal cell carcinoma, lipogenesis, alpha-ketoglutarate, PDK1, ATP citrate lyase, glutaminase inhibitors, tumor xenografts, mass action
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Carbon Isotopes, Carboxylic Acids, Carcinoma, Renal Cell, Citrates, Glutamine, Humans, Gas Chromatography-Mass Spectrometry, Models, Biological, Magnetic Resonance Spectroscopy, Oxidation-Reduction, Extracellular Fluid, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein
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