Carbonic Anhydrases: Role in pH Control and Cancer

Abstract

The pH of the tumor microenvironment drives the metastatic phenotype and chemotherapeutic resistance of tumors. Understanding the mechanisms underlying this pH-dependent phenomenon will lead to improved drug delivery and allow the identification of new therapeutic targets. This includes an understanding of the role pH plays in primary tumor cells, and the regulatory factors that permit cancer cells to thrive. Over the last decade, carbonic anhydrases (CAs) have been shown to be important mediators of tumor cell pH by modulating the bicarbonate and proton concentrations for cell survival and proliferation. This has prompted an effort to inhibit specific CA isoforms, as an anti-cancer therapeutic strategy. Of the 12 active CA isoforms, two, CA IX and XII, have been considered anti-cancer targets. However, other CA isoforms also show similar activity and tissue distribution in cancers and have not been considered as therapeutic targets for cancer treatment. In this review, we consider all the CA isoforms and their possible role in tumors and their potential as targets for cancer therapy.

A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells

“…Indeed, it has been shown that pH i in the cytoplasm of tumor cells (pH 7. 2-7.4) is similar to that of normal cells (10,11) . However, the pH e surrounding tumor cells is strongly acidic (pH 6.5-6.8) (11).…”

“…There is additional evidence that CA IX forms functional interactions with specific ion transporters accelerating their activity (24,29,30). It has been hypothesized that CA IX forms a metabolon with these transporters and CA II to maintain the glycolytic phenotype by 'cycling' substrates between tumors cells and the microenvironment to regulated pH i (10,16,23,24,(29)(30)(31). Our lab, and others, have also hypothesized that CA IX serves to regulate pH e by responding to changes in substrate concentration (10,19,20).…”

“…In the first of two independent stages, CO 2 undergoes hydration within the active site to form a Zn-bound bicarbonate, which is subsequently exchanged for H 2 The α-class of CAs is made up of twelve catalytically active isoforms that differ in tissue distribution and subcellular localization (23). Of the human isoforms, only membrane bound carbonic anhydrase IX (CA IX) and carbonic anhydrase XII (CA XII) have been linked to cancer (10,23) Both isoforms display their catalytic domains from the exofacial side of the plasma membrane (22). More attention has been placed on CA IX, as this isoform is upregulated by hypoxia, is associated with more aggressive forms of cancer, and is predictive of poor patient outcome (24)(25)(26)(27).…”

“…It has been hypothesized that CA IX forms a metabolon with these transporters and CA II to maintain the glycolytic phenotype by 'cycling' substrates between tumors cells and the microenvironment to regulated pH i (10,16,23,24,(29)(30)(31). Our lab, and others, have also hypothesized that CA IX serves to regulate pH e by responding to changes in substrate concentration (10,19,20). As pH e decreases, CA IX sequesters protons in the form of CO 2 and H 2 O through the dehydration reaction (27,32,33).…”

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

“…A wealth of functional studies has been accumulated over the years on hCA IX, showing that this enzyme is actively involved in survival, proliferation, invasion, and metastasis of cancer cells by means of several mechanisms, which involve all its different domains. 7,9,52,80,81 Among these mechanisms, the tumor pH regulation carried out by the CA domain 80,82 plays a key role in survival, migration, and invasion of cancer cells. 24,[83][84][85][86] The involvement of hCA IX in regulating pH of hypoxic tumor cells can be schematically summarized as follows ( Figure 5).…”