9.1 Introduction 256

9.2 Identification, Structure and Distribution of CA IX 257

9.3 Regulation of CA IX Expression 259

9.4 CA IX as a Marker of Tumor Hypoxia 260

9.5 Identification, Distribution and Regulation of CA XII 263

9.6 Catalytic Properties and Proposed Roles of CA IX and CA XII 265

9.7 Influence of Extracellular pH on Tumor Progression and Possible Implication of CA Activity 270

9.8 CA Inhibition as an Approach to Anticancer Therapy 270

9.9 Inhibition Profile of CA IX 272

9.10 Conclusions 274

Acknowledgments 274

References 274

Changes in tumor metabolism and microenvironment connected with adaptation of cells to hypoxia are important components of tumor progression. Transmembrane carbonic anhydrase (CA) isozymes CA IX and CA XII containing extracellular enzyme active sites appear to participate in this process via their ability to catalyze hydration of CO2 to bicarbonate and a proton and regulate intratumoral pH. In addition, CA IX, possessing a unique N-terminal domain, can perturb E-cadherin-mediated cell-cell adhesion via interaction with b-catenin and potentially contribute to tumor invasion. CA IX shows restricted expression in normal tissues but is tightly associated with different types of tumors, mostly because of its strong induction by tumor hypoxia that involves HIF-1 binding to a hypoxia response element in the CA9 promoter. CA IX has been proposed to serve as a marker of tumor hypoxia and its predictive and prognostic potential has been demonstrated in numerous clinical studies. CA XII is present in many normal tissues and overexpressed in some tumors. It is also induced by hypoxia, but the underlying molecular mechanism

© 2004 by CRC Press LLC 255

remains undetermined. Both CA IX and CA XII are negatively regulated by von Hippel-Lindau tumor suppressor protein and their expression in renal cell carcinomas is related to inactivating mutations of the VHL gene. High catalytic activity of these two CA isoforms supports their role in acidification of the tumor microenvironment, which facilitates acquisition of the metastatic phenotype. Therefore, modulating extracellular tumor pH by inhibiting CA activity is a promising approach to anticancer therapy. Sulfonamide CAIs have been shown to compromise tumor cell proliferation and invasion in vitro and improve the effect of conventional chemotherapy in vivo; however, their precise targets are not known. Because the tumor-associated CA IX is a sulfonamide-avid enzyme, it is possible that at least some of the observed anticancer effects of the sulfonamide inhibitors are mediated by inhibition of this CA isoform. Moreover, the inhibition profile of CA IX differs from those of CA I, II and IV, indicating that the design and synthesis of CA IX-specific inhibitors with therapeutic properties could in principle be feasible.

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