The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
The SIRT1/HIF2α Axis Drives Reductive Glutamine Metabolism under Chronic Acidosis and Alters Tumor Response to Therapy
Published version of a preprint
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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Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy
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Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
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Glutamine addiction: a new therapeutic target in cancer
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Acidity Generated by the Tumor Microenvironment Drives Local Invasion
Estrella, V. C., Chen, T., Lloyd, M. C., Wojtkowiak, J. W., Cornnell, H. H., Ibrahim‐Hashim, A., Bailey, K. M., Balagurunathan, Y., Rothberg, J. M., Sloane, B. F., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2796 · Cited by 1,404
Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer
DeBerardinis, R. J., & Cheng, T. (2010) · Oncogene · doi:10.1038/onc.2009.358 · Cited by 1,365
Glutamine and cancer: cell biology, physiology, and clinical opportunities
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The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis
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The Acidic Tumor Microenvironment as a Driver of Cancer
Boedtkjer, E., & Pedersen, S. F. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034627 · Cited by 1,293
NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism
Xiao, W., Wang, R., Handy, D. E., & Loscalzo, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7216 · Cited by 1,062
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021
Tumour acidosis: from the passenger to the driver's seat
Corbet, C., & Féron, O. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.77 · Cited by 1,028
Self-citationMonocarboxylate transporters in cancer
Payen, V. L., Mina, E., Hée, V. F. V., Porporato, P. E., & Sonveaux, P. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.07.006 · Cited by 688
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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