Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH
Open accessAbstract
Acidic extracellular pH (pHe) is a typical attribute of a tumor microenvironment, which has an impact on cancer development and treatment outcome. It was believed to result from an accumulation of lactic acid excessively produced by glycolysis. However, metabolic profiles of glycolysis-impaired tumors have revealed that CO2 is a significant source of acidity, thereby indicating a contribution of carbonic anhydrase (CA). The tumor-associated CA IX isoform is the best candidate, because its extracellular enzyme domain is highly active, expression is induced by hypoxia and correlates with poor prognosis. This study provides the first evidence for the role of CA IX in the control of pHe. We show that CA IX can acidify the pH of the culture medium in hypoxia but not in normoxia. This acidification can be perturbed by deletion of the enzyme active site and inhibited by CA IX-selective sulfonamides, which bind only to hypoxic cells containing CA IX. Our findings suggest that hypoxia regulates both expression and activity of CA IX in order to enhance the extracellular acidification, which may have important implications for tumor progression.
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Medium deoxygenation in cell cultures of human cancer cell lines induced the expression and activity of carbonic anhydrases, which resulted in enhanced acidification of the culture medium.
“Švastová and others showed that medium deoxygenation in cell cultures of human cancer cell lines induced the expression and activity of carbonic anhydrases, which resulted in enhanced acidification of the culture medium (Švastová et al., 2004).”
From Toward Best Practices for Controlling Mammalian Cell Culture Environments (2022) · cites this paper as Švastová et al., 2004
Section 3.3 (page unavailable) reports that hypoxic HeLa and SiHa cancer-cell cultures had lower medium pH, elevated CA IX expression, and catalytically active CA IX; a CA IX-selective inhibitor partially reduced the acidosis. Section 3.5 (page unavailable) further supports CA IX's role in acidification. The claim overgeneralizes this finding to carbonic anhydrases in the plural and presents them as the sole cause, whereas the paper studies CA IX and describes its contribution as partial. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCarbonic anhydrase expression, especially the CAIX isoform, increases during hypoxia.
“Expression of carbonic anhydrases, in particular the CAIX isoform, is elevated during hypoxia (Svastova et al., 2004).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Svastova et al., 2004
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Self-citation
- Authors
- Švastová, E., Hulı́ková, A., Rafajová, M., Zat'ovičová, M., Gibadulinová, A., Casini, A., Cecchi, A., Scozzafava, A., Supuran, C. T., Pastorek, J., & Pastoreková, S.
- Affiliations
- Slovak Academy of Sciences (SK)
- University of Florence (IT)
- ORCID
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2004-10-28
- Volume
- 577
- Issue
- 3
- Pages
- 439-445
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W1990331048
- Cited by
- 711
- References
- 32
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 17 · 2023: 31 · 2022: 22 · 2021: 33 · 2020: 37 · 2019: 27 · 2018: 35 · 2017: 39 · 2016: 22 · 2015: 47 · 2014: 46 · 2013: 43 · 2012: 36
- FWCI
- 12.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Bayer HealthCare
- Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- carbonic anhydrase IX, tumor hypoxia, extracellular pH, tumor acidosis, sulfonamide inhibitors, glycolysis, tumor progression
- MeSH terms
- Carbonic Anhydrase IX, Acidosis, Animals, Antigens, Neoplasm, Binding Sites, Carbonic Anhydrases, Cell Line, Cloning, Molecular, Culture Media, Dogs, Enzyme Inhibitors, HeLa Cells, Humans, Hydrogen-Ion Concentration, Isoenzymes, Precipitin Tests, Sulfonamides, Time Factors, Biomarkers, Tumor, Molecular Structure, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Sequence Deletion, Protein Structure, Tertiary, Biotinylation
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