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[摘要]：The acid-base balance of cells is related to the concentration of free H(+) ions. These are highly reactive, and their intracellular concentration must be regulated to avoid detrimental effects to the cell. H(+) ion dynamics are influenced by binding to chelator substances ('buffering'), and by the production, diffusion and membrane-transport of free H(+) ions or of the H(+)-bound chelators. Intracellular pH (pH(i)) regulation aims to balance this system of diffusion-reaction-transport processes at a favourable steady-state pH(i). The ability of cells to regulate pH(i) may set a limit to tissue growth and can be subject to selection pressures. Cancer cells have been postulated to respond favourably to such selection pressures by evolving a better means of pH(i) regulation. A particularly important feature of tumour pH(i) regulation is acid-extrusion, which involves H(+)-extrusion and HCO(3)(-)-uptake by membrane-bound transporter-proteins. Extracellular CO(2)/HCO(3)(-) buffer facilitates these membrane-transport processes. As a mobile pH-buffer, CO(2)/HCO(3)(-) protects the extracellular space from excessive acidification that could otherwise inhibit further acid-extrusion. CO(2)/HCO(3)(-) also provides substrate for HCO(3)(-)-transporters. However, the inherently slow reaction kinetics of CO(2)/HCO(3)(-) can be rate-limiting for acid-extrusion. To circumvent this, cells can express extracellular-facing carbonic anhydrase enzymes to accelerate the attainment of equilibrium between CO(2), HCO(3)(-) and H(+). The acid-extrusion apparatus has been proposed as a target for anti-cancer therapy. The major targets include H(+) pumps, Na(+)/H(+) exchangers and carbonic anhydrases. The effectiveness of such therapy will depend on the correct identification of rate-limiting steps in pH(i) regulation in a specific type of cancer. |
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