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J. Biol. Chem., Vol. 283, Issue 29, 20473-20483, July 18, 2008

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Tumor-associated Carbonic Anhydrase 9 Spatially Coordinates Intracellular pH in Three-dimensional Multicellular Growths^*

Pawel Swietach, Simon Wigfield, Philip Cobden, Claudiu T. Supuran^¶, Adrian L. Harris¹, and Richard D. Vaughan-Jones¹²

From the Department of Physiology, Anatomy, and Genetics, Burdon Sanderson Cardiac Science Centre, Oxford OX1 3PT, United Kingdom, the Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom, and the ^¶Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze, Firenze I-50019, Italy

CA9 is a membrane-tethered, carbonic anhydrase (CA) enzyme, expressed mainly at the external surface of cells, that catalyzes reversible CO₂ hydration. Expression is greatly enhanced in many tumors, particularly in aggressive carcinomas. The functional role of CA9 in tumors is not well established. Here we show that CA9, when expressed heterologously in cultured spheroids (0.5-mm diameter, 25,000 cells) of RT112 cells (derived from bladder carcinoma), induces a near-uniform intracellular pH (pH_i) throughout the structure. Dynamic pH_i changes during displacements of superfusate CO₂ concentration are also spatially coincident (within 2 s). In contrast, spheroids of wild-type RT112 cells lacking CA9 exhibit an acidic core (0.25 pH_i reduction) and significant time delays (9 s) for pH_i changes in core versus peripheral regions. pH_i non-uniformity also occurs in CA9-expressing spheroids after selective pharmacological inhibition of the enzyme. In isolated RT112 cells, pH_i regulation is unaffected by CA9 expression. The influence of CA9 on pH_i is thus only evident in multicellular tissue. Diffusion-reaction modeling indicates that CA9 coordinates pH_i spatially by facilitating CO₂ diffusion in the unstirred extracellular space of the spheroid. We suggest that pH_i coordination may favor survival and growth of a tumor. By disrupting spatial pH_i control, inhibition of CA9 activity may offer a novel strategy for the clinical treatment of CA9-associated tumors.

Received for publication, February 19, 2008 , and in revised form, April 30, 2008.

^* This work was supported by the British Heart Foundation (to R. D. V.-J.), Cancer Research UK (to A. L. H.), and European Framework 6 EUROXY (to A. L. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text, equations, Figs. S1 and S2, and Table S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Tel./Fax: 44-1865-272451; E-mail: richard.vaughan-jones{at}dpag.ox.ac.uk.

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