Background/Aims: Tumor cells produce a large amount of acidic metabolites due to their high metabolic condition. However, cytosolic pH (pHc) of tumor cells is identical to or even slightly higher than that of normal cells. To maintain pHc at a normal or higher level, tumor cells would have to have higher expression and/or activity of H+ transporting systems than normal cells. The purpose of the present study was to identify effects of ethyl-isopropyl amiloride (EIPA, an inhibitor of Na+/H+ exchanger (NHE)) on proliferation of human gastric cancer MKN28 cells. Methods: Effects of EIPA on proliferation, pHc, [Cl-]c and expression of proteins regulating cell cycle and MAPKs were studied in MKN28 expressing NHE exposed to EIPA for 48 h. Results: EIPA suppressed proliferation of MKN28 cells by causing G₀/G1 arrest without any significant effects on pHc, but associated with reduction of [Cl-]c. Although EIPA alone had no effects on pHc, EIPA co-applied with DIDS (an inhibitor of Cl-/HCO3- exchangers; i.e., anion exchanger (AE) and Na+-driven Cl-/HCO3- exchanger (NDCBE)) reduced pHc, suggesting that DIDS-sensitive Cl-/HCO3- transporters such as AE and/or NDCBE keep pHc normal by stimulating HCO3- uptake coupled with Cl- release under an NHE-inhibited condition. EIPA-induced lowered [Cl-]c up-regulated expression of p21associated with phosphorylation of MAPKs, suppressing proliferation associated with G₀/G1 arrest. Conclusions : EIPA suppressed proliferation of MKN28 cells through up-regulation of p21 expression via reduction of [Cl-]c as a result from DIDS-sensitive Cl-/HCO3- exchanger-mediated compensation for keeping pHc normal under an NHE-inhibited condition. This is the first study revealing that an NHE inhibitor suppressed the proliferation of cancer cells by reducing [Cl-]c but not pHc.

Keywords:
p21, Cell cycle, Anion exchanger, MAPK, Rb
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© 2012 S. Karger AG, Basel
2012
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