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New Insights Into the Physiological Role of Carbonic Anhydrase IX in Tumour Ph Regulation

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New Insights Into the Physiological Role of Carbonic Anhydrase IX in Tumour Ph Regulation Oncogene (2010) 29, 6509–6521 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation P Swietach1, A Hulikova1, RD Vaughan-Jones1,3 and AL Harris2,3 1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK and 2Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK In this review, we discuss the role of the tumour-associated acidity, commonly expressed using the pH scale. A carbonic anhydrase isoform IX (CAIX) in the context of particularly important class of pH-sensitive molecules is pH regulation. We summarise recent experimental find- protein because of the strong link between protonation ings on the effect of CAIX on cell growth and survival, and state, tertiary structure and functional output. The þ present a diffusion-reaction model to help in the assess- responsiveness to pH depends on H affinity (KH), ment of CAIX function under physiological conditions. bestowed on the protein by the chemistry of its amino CAIX emerges as an important facilitator of acid acid residues. For many proteins, KH is numerically diffusion and acid transport, helping to overcome large close to physiological [H þ ], thus even small displace- cell-to-capillary distances that are characteristic of solid ments from ‘normal’ intracellular pH (pHi) can sig- tumours. The source of substrate for CAIX catalysis is nificantly alter cellular biochemistry. H þ ions serve as likely to be CO2, generated by adequately oxygenated universal and potent modulators of virtually all aspects mitochondria or from the titration of metabolic acids with of life. Through the breadth of their effects, H þ ions are À HCO3 taken up from the extracellular milieu. The appropriate signalling molecules for coordinating com- relative importance of these pathways will depend on plex cell programmes. For instance, moderately alkaline oxygen and metabolite availability, the spatiotemporal pHi is permissive for cell proliferation (Pouyssegur et al., patterns of the cell’s exposure to hypoxia and on the 1984; Chambard and Pouyssegur, 1986; Gillies et al., regulation of metabolism by genes. This is now an 1990; Gillies et al., 1992). It is not surprising that proper important avenue for further investigation. The impor- pHi regulation is of fundamental importance to all cells. tance of CAIX in regulating tumour pH highlights the Specialised mechanisms for pHi regulation have protein as a potential target for cancer therapy. evolved to fine-tune acid/base balance appropriately Oncogene (2010) 29, 6509–6521; doi:10.1038/onc.2010.455; for on-going cellular physiology. A major challenge to published online 4 October 2010 pHi house keeping is the large disparity between the target H þ ion concentration, typically between 50 and Keywords: cancer; pH; carbonic anhydrase IX; acid/ 100 nM, and the acid/base challenges, as high as base transport; buffers millimolar per minute, that disturb pHi. Among these acid/base loads is cellular respiration, which produces þ H -yielding CO2 or lactic acid. The most metabolically active cells are expected to express the most powerful The fundamental importance of acid/base balance pHi regulating apparatus. Cancer cells, for instance, are characterised by a very high metabolic rate (Gatenby Cellular function, growth and development arise from a and Gillies, 2004). The alkaline pHi measured in diversity of interlinked biochemical processes. The tumours with nuclear magnetic resonance (Griffiths proper orchestration of these unitary events is per- et al., 1981; Gillies et al., 2004) suggests that these cells formed by a hierarchy of signalling cascades, involving are well equipped to deal with excess H þ ions. both small ions (such as calcium) as well as more complex molecules (such as G-proteins). The potency and scope of these signals depends on the responsiveness of target molecules. Many biological molecules are weak Buffering reactions and membrane transport regulate acids or weak bases that can release or bind H þ ions intracellular pH (protons), respectively. The protonation state (and hence charge) of these molecules will depend on ambient Cells contain a high concentration of weak acids and weak bases—such as proteins, amino acids and phos- Correspondence: Dr P Swietach, Department of Physiology, Anatomy phates—which results in the intracellular milieu having and Genetics, University of Oxford, Sherrington Building, South Parks a high pH buffering power (Boron, 2004). Buffers are Road, Oxford OX1 3PT, UK. necessary to ‘dampen’ pHi displacements in response to E-mail: [email protected] þ 3Joint senior authors. H production (or consumption) that takes place at Received 16 July 2010; revised 30 August 2010; accepted 31 August 2010; distinct loci within cells, such as mitochondria or the published online 4 October 2010 surface membrane. In the presence of buffers, even Carbonic anhydrase IX in tumour pH regulation P Swietach et al 6510 millimolar concentrations of acid (or base) inflict merely Therefore, pHi sensitivity must be built into the nanomolar changes in free H þ ion concentration apparatus for regulating acid/base balance. The fidelity (equivalent to changing pHi by a fraction of a unit). of this pHi-sensing mechanism relies on good diffusive Most cells usually undergo periods of sustained acid coupling across the cell, particularly between the bulk loading. Buffering does not eliminate the acid/base cytoplasm and the cell membrane. The diffusive H þ flux problem, but merely acts as a temporary repository for must match H þ production with H þ extrusion (and H þ ions. Chronic acid production (for example, by similarly, H þ depletion with H þ loading). However, respiration) can deplete protonatable buffer sites. To because of the high intracellular buffering capacity, avoid this shortfall in buffering power, excess H þ ions, most H þ ions are bound to buffer molecules and can above a certain desired [H þ ] level, must be extruded diffuse only as fast as the H þ buffer complex (Irving from cells. In its simplest case, acid extrusion should et al., 1990; Vaughan-Jones et al., 2002; Swietach et al., match metabolic acid production. High-charge density 2003). An indispensible role for smaller buffer mole- precludes H þ ions themselves from crossing the lipid cules, such as amino acids, dipeptides, phosphates and À bilayer of membranes. To overcome this permeability carbon dioxide/bicarbonate (CO2/HCO3), is to shuttle obstacle, H þ ions must be shuttled across the membrane H þ ions within cells (Figure 1a). These are needed to in a permeant form by transport proteins. As the offset the diffusive restrictions imposed by heavier H þ transport of H þ ions across the membrane may require buffers, such as proteins. an input of energy, pHi regulation usually involves An alternative buffer/transporter arrangement for þ À primary (for example, H ATPase) or secondary (for pHi regulation relies uniquely on the CO2/HCO3 buffer example, Na þ /H þ exchanger (NHE)) active transpor- system (Figure 1b). This buffer, often labelled as ters (Figure 1a; Martinez-Zaguilan et al., 1993; Lee and physiological, is a major component of buffering Tannock, 1998; McLean et al., 2000; Boron, 2004; capacity (Leem et al., 1999; Boron, 2004; Alper, 2006). Chiche et al., 2010). Unlike many other buffer systems, its protonated form Acid extrusion must remain responsive to even the (CO2) is usually freely permeant across the membrane smallest change in metabolic rate. Moreover, under lipid bilayer. Transmembrane flux of CO2 is therefore a certain circumstances, cells may incur a deficiency of H þ disguised form of H þ flux that does not require a ions and require acid uptake (for example, by ClÀ/H þ - protein transporter, although it can be enhanced by equivalent transport; Vasseur et al., 1989; Sun et al., aquaporins (Nakhoul et al., 1998). To enable this system 1996; Niederer et al., 2008), rather than acid extrusion. to regulate pHi effectively, flux of CO2 must be matched À by counter flux of HCO3. Bicarbonate ions are À membrane impermeant and therefore active HCO3 transport at the cell membrane is required to maintain À intracellular CO2/HCO3 composition (Figure 1b). For the purpose of this review, the two schemes of À pHi regulation are referred to as HCO3 dependent and À HCO3 independent with reference to the species of ion that is transported across the cell membrane. It is À noteworthy that, even in the absence of HCO3 À transporters, CO2/HCO3 buffer can participate in pH regulation by spatially shuttling H þ ions to and from H þ transporters (Spitzer et al., 2002; Swietach et al., 2007). À The versatility of the CO2/HCO3 buffer system can be limited by the slow kinetics of CO2 hydration and the reverse dehydration reaction. Without catalysis, the À slow interchange between CO2 and HCO3 could impede H þ shuttling within the cell and across the membrane. For this reason, most cells express carbonic anhydrase (CA) enzymes, which catalyse the reversible reaction, À þ CO2 þ H2O2HCO3 þ H . Some CA isoforms have an Figure 1 Cellular mechanisms for removing intracellular acid intracellular catalytic site (for example, CAI, CAII, þ À involve pH buffers and membrane H or HCO3 transporters. (a) CAIII and so on), whereas others (for example, CAIV, À þ HCO3-independent mechanism: Intracellular H ions are extruded CAIX, CAXII, CAXIV) catalyse the reaction at the across the cell membrane by means of an H þ transporter (hexagon), such as Na þ /H þ exchange or H þ lactate cotransport. extracellular surface of the cells (Chegwidden et al., The transporter is supplied with H þ ions by protonated buffers 2000; Supuran, 2008). þ À (HBuf) that facilitate intracellular H diffusion. (b) HCO3- Regulation of pHi goes beyond the cell.
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