Figure 1

Figure 1: Ion transporters involved in regulation of cytosolic Cl^-environments and roles of cytosolic Cl^- in cell function. Na⁺/H⁺ exchanger (NHE) has no direct contribution to intracellular Cl^- environments, since NHE directly participates in Na⁺ uptake coupling with H⁺ extrusion. However, application of an inhibitor of NHE, EIPA, lowers the cytosolic Cl^- concentration ([Cl^-]_c) without any effect on cytosolic pH (pH_c) [31]. The EIPA-caused lowered [Cl^-]_c would be due to activation of Na⁺-driven Cl^-/HCO₃ - exchanger (NDCBE) compensating the EIPA-caused acute lowered pH_c [31]. For example, in cancer cells mitochondria function is low, leading to low production of CO₂. This means that contents of H⁺ and HCO₃ - induced by CO₂ from mitochondria are low in cytosolic space of cancer cells. On the one hand, cancer cells produce a lot of H⁺ via glycolysis, being converted to CO₂ and H2O with HCO₃ - a carbonic anhydrase-mediated process, resulting in lowered HCO₃ - in cytosolic space. Taken together, the amount of HCO₃ - in cytosolic space of cancer cells is much lower than that in normal cells. Thus, activation of ion transporters taking HCO₃ - up into the cytosolic space such as NDCBE, which extrudes cytosolic Cl^- using electrochemical gradient of Na⁺, in cancer cells with a low HCO₃ - condition is much effective in lowering [Cl^-]_c than normal cells. Namely, inhibition of NHE and activation of NDCBE would effectively decrease [Cl^-]_c, under a condition with low mitochondria function occurring in cancer cells. This leads cancer cells to G₀/G₁ arrest via a MPKs-p21-Rb pathway and autophagy dysfunction via elevation of intra-lysosomal pH. Based on the information described above, some drugs modifying activity of ion transporters involved in regulation of cytosolic Cl^- environments would be useful for anticancer therapies.
AE, Cl^-/HCO₃ - exchanger; ClC-7, 2Cl^-/1H⁺ exchange; MPKs, mitogen-activated protein kinases; NBC, Na⁺-HCO₃ - cotransporter; NDCBE, Na⁺-driven Cl^-/HCO₃ - exchanger; NHE, Na⁺/H⁺ exchanger; NKCC, Na⁺-K⁺-2Cl^- cotransporter; Rb, retinoblastoma protein; V-ATPase, V-type H⁺-ATPase.