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The SIRT1/HIF2α Axis Drives Reductive Glutamine Metabolism under Chronic Acidosis and Alters Tumor Response to Therapy
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Abstract
Extracellular tumor acidosis largely results from an exacerbated glycolytic flux in cancer and cancer-associated cells. Conversely, little is known about how tumor cells adapt their metabolism to acidosis. Here, we demonstrate that long-term exposure of cancer cells to acidic pH leads to a metabolic reprogramming toward glutamine metabolism. This switch is triggered by the need to reduce the production of protons from glycolysis and further maintained by the NAD+-dependent increase in SIRT1 deacetylase activity to ensure intracellular pH homeostasis. A consecutive increase in HIF2α activity promotes the expression of various transporters and enzymes supporting the reductive and oxidative glutamine metabolism, whereas a reduction in functional HIF1α expression consolidates the inhibition of glycolysis. Finally, in vitro and in vivo experiments document that acidosis accounts for a net increase in tumor sensitivity to inhibitors of SIRT1 and glutaminase GLS1. These findings highlight the influence that tumor acidosis and metabolism exert on each other. Cancer Res; 74(19); 5507–19. ©2014 AACR.
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“Furthermore, long-term exposure of cancer cells to acidic extracellular conditions induces metabolic reprogramming toward glutamine metabolism via HIF-2α activity71.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [71]
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Metadata
- Authors
- Corbet, C., Draoui, N., Polet, F., Pinto, A., Drozak, X., Riant, O., & Feron, O.
- Affiliations
- UCLouvain (BE)
- 1Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
- Venue
- Cancer Research
- Published
- 2014-09-30
- Volume
- 74
- Issue
- 19
- Pages
- 5507-5519
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2099667863
- Cited by
- 169
- References
- 37
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 19 · 2023: 12 · 2022: 20 · 2021: 16 · 2020: 23 · 2019: 20 · 2018: 7 · 2017: 8 · 2016: 9 · 2015: 10
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- tumor acidosis, SIRT1, HIF-2α, HIF-1α, glutamine metabolism, glycolysis, intracellular pH homeostasis, NAD+-dependent deacetylation, SIRT1 inhibitors, tumor metabolic reprogramming, cancer therapy response
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Acidosis, Chronic Disease, Glucose, Glutamine, Glycolysis, Humans, Neoplasms, Cell Line, Tumor, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Sirtuin 1
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