Details

Autor(en) / Beteiligte

• Svastova, Eliska
• Witarski, Wojciech
• Csaderova, Lucia
• Kosik, Ivan
• Skvarkova, Lucia
• Hulikova, Alzbeta
• Zatovicova, Miriam
• Barathova, Monika
• Kopacek, Juraj
• Pastorek, Jaromir
• Pastorekova, Silvia

Titel

Carbonic Anhydrase IX Interacts with Bicarbonate Transporters in Lamellipodia and Increases Cell Migration via Its Catalytic Domain

Ist Teil von

• The Journal of biological chemistry, 2012-01, Vol.287 (5), p.3392-3402

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Carbonic anhydrase IX (CA IX) is a hypoxia-induced cell surface enzyme expressed in solid tumors, and functionally involved in acidification of extracellular pH and destabilization of intercellular contacts. Since both extracellular acidosis and reduced cell adhesion facilitate invasion and metastasis, we investigated the role of CA IX in cell migration, which promotes the metastatic cascade. As demonstrated here, ectopically expressed CA IX increases scattering, wound healing and transwell migration of MDCK cells, while an inactive CA IX variant lacking the catalytic domain (ΔCA) fails to do so. Correspondingly, hypoxic HeLa cells exhibit diminished migration upon inactivation of the endogenous CA IX either by forced expression of the dominant-negative ΔCA variant or by treatment with CA inhibitor, implying that the catalytic activity is indispensable for the CA IX function. Interestingly, CA IX improves cell migration both in the absence and presence of hepatocyte growth factor (HGF), an established inducer of epithelial-mesenchymal transition. On the other hand, HGF up-regulates CA IX transcription and triggers CA IX protein accumulation at the leading edge of lamellipodia. In these membrane regions CA IX co-localizes with sodium bicarbonate co-transporter (NBCe1) and anion exchanger 2 (AE2) that are both components of the migration apparatus and form bicarbonate transport metabolon with CA IX. Moreover, CA IX physically interacts with AE2 and NBCe1 in situ, as shown here for the first time. Thus, our findings suggest that CA IX actively contributes to cell migration via its ability to facilitate ion transport and pH control at protruding fronts of moving cells. Background: Hypoxia-induced CA IX contributes to pH control in tumor cells, and control of pH is important for cell migration. Results: CA IX increases migration through catalytic domain and interacts with bicarbonate transporters in lamellipodia. Conclusion: CA IX is an active component of the molecular machinery that facilitates migration of tumor cells through pH regulation at the leading edge membranes. Significance: This identifies CA IX as a target to suppress cell migration and reduce tumor aggressiveness.