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

FEBS Letters - Tập 577 Số 3 - Trang 439-445 - 2004
Eliška Švastová1, Alžbeta Hulı́ková1, Monika Baráthová1, Miriam Zaťovičová1, Adriana Gibadulinová1, Angela Casini2, Alessandro Cecchi2, Andrea Scozzafava2, Claudiu T. Supuran2, Jaromı́r Pastorek1, Silvia Pastoreková1
1Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05 Bratislava, Slovak Republic
2Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy

Tóm tắt

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.

Từ khóa


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FEBS Letters

Tập 577 Số 3

439-445

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