Figure 11.

Association between high glycolytic flux and extracellular pH (pHe) gradient formation by carbonic anhydrase, as well as proton pump and exchangers. Glycolysis-associated lactate generation promotes hypoxia-inducible factor-1a (HIF-1α) activation and HIF-1α dependent transcription of several proton channels and exchangers. Extrusion of protons (H⁺) by these regulators contributes to a concomitant extracellular acidification (pHe: 6.8) and intracellular alkalinization (pHi: 7.2) in growing tumor cells. Additional source of tumor microenvironment acidity is the activity of carbonic anhydrase IX (CAIX). CAIX-dependent hydration of carbon dioxide (CO₂) – predominantly generated by the oxidative branch of the pentose phosphate pathway (ox-PPP) and to a lesser extent by TCA cycle – delivers protons (H⁺) and hydrogen carbonate (HCO₃⁻) ions. Subsequent uptake of HCO₃⁻ by Na⁺-dependent bicarbonate (NBC) transporter and anion exchanger 2 (AE2), replenishes the intracellular HCO₃⁻. Titration of HCO₃⁻ by intracellular H⁺ ions, produced by glycolysis, results in the formation of CO₂ which rapidly diffuses across the plasma membrane, where it meets CAIX. MCT: monocarboxylate transporter, V-ATPase: vacuolar-type proton ATPase, NHE-1: sodium/hydrogen exchanger 1, AE2: anion exchanger 2, NBC: sodium/bicarbonate (Na⁺/HCO₃⁻) co-transporter, CAIX: carbonic anhydrase 9.