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Hypoxia activates the capacity of tumor‐associated carbonic anhydrase IX to acidify extracellular pH
Author(s) -
Švastová Eliška,
Hulı́ková Alžbeta,
Rafajová Monika,
Zat'ovičová Miriam,
Gibadulinová Adriana,
Casini Angela,
Cecchi Alessandro,
Scozzafava Andrea,
Supuran Claudiu T.,
Pastorek Jaromı́r,
Pastoreková Silvia
Publication year - 2004
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.10.043
Subject(s) - extracellular , carbonic anhydrase , glycolysis , hypoxia (environmental) , enzyme , chemistry , biochemistry , intracellular ph , tumor microenvironment , microbiology and biotechnology , biology , cancer research , oxygen , tumor cells , organic chemistry
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 CO 2 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.