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Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH

Svastova, E., Hulikova, A., Rafajova, M., Zat'ovicova, M., Gibadulinova, A., Casini, Angela, Cecchi, A., Scozzafava, A., Supuran, C.T., Pastorek, J. and Pastorekova, S. 2004. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Letters 577 (3) , pp. 439-445. 10.1016/j.febslet.2004.10.043

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Acidic extracellular pH (pHe) is a typical attribute of a tumor microenviroment, 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: AE, anion exchanger; CA, carbonic anhydrase; ΔCA, deletion mutant of CA IX lacking the catalytic domain; CAI, carbonic anhydrase inhibitor; ΔPG, deletion mutant of CA IX lacking the proteoglycan-like domain; HIF, hypoxia inducible factor; MAb, monoclonal antibody; pHe, extracellular pH; Tumor microenvironment; Acidosis; Carbonic anhydrase IX; Hypoxia; Sulfonamide
Publisher: Wiley-Blackwell
ISSN: 0014-5793
Date of Acceptance: 17 October 2004
Last Modified: 23 Jul 2020 01:47

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