Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH.
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.
Svastová
Eliska
E
Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05 Bratislava, Slovak Republic.
Hulíková
Alzbeta
A
Rafajová
Monika
M
Zat'ovicová
Miriam
M
Gibadulinová
Adriana
A
Casini
Angela
A
Cecchi
Alessandro
A
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
Pastorek
Jaromír
J
Pastoreková
Silvia
S
D000138:Acidosis / Q000209:etiology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D014408:Biomarkers, Tumor; D019921:Biotinylation; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D003001:Cloning, Molecular; D003470:Culture Media; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000378:metabolism*; D015394:Molecular Structure; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D003470:Culture Media; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases