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首页> 外文期刊>Cellular Physiology and Biochemistry >An Inhibitor of Na+/H+ Exchanger (NHE), Ethyl-Isopropyl Amiloride (EIPA), Diminishes Proliferation of MKN28 Human Gastric Cancer Cells by Decreasing the Cytosolic Cl- Concentration via DIDS-Sensitive Pathways
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An Inhibitor of Na+/H+ Exchanger (NHE), Ethyl-Isopropyl Amiloride (EIPA), Diminishes Proliferation of MKN28 Human Gastric Cancer Cells by Decreasing the Cytosolic Cl- Concentration via DIDS-Sensitive Pathways

机译：Na + / H +交换剂（NHE），乙基异丙基阿米洛利（EIPA）抑制剂通过通过DIDS敏感途径降低细胞内Cl-浓度来减少MKN28人胃癌细胞的增殖。

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biBackground/Aims /i/bTumor cells produce a large amount of acidic metabolites due to their high metabolic condition. However, cytosolic pH (pHsubc/sub) of tumor cells is identical to or even slightly higher than that of normal cells. To maintain pHsubc/sub at a normal or higher level, tumor cells would have to have higher expression and/or activity of Hsup+/sup transporting systems than normal cells. The purpose of the present study was to identify effects of ethyl-isopropyl amiloride (EIPA, an inhibitor of Nasup+/sup/Hsup+/sup exchanger (NHE)) on proliferation of human gastric cancer MKN28 cells. biMethods /i/bEffects of EIPA on proliferation, pHsubc/sub, [Clsup-/sup]subc/sub and expression of proteins regulating cell cycle and MAPKs were studied in MKN28 expressing NHE exposed to EIPA for 48 h. biResults /i/bEIPA suppressed proliferation of MKN28 cells by causing G₀/Gsub1/sub arrest without any significant effects on pHsubc/sub, but associated with reduction of [Clsup-/sup]subc/sub. Although EIPA alone had no effects on pHsubc/sub, EIPA co-applied with DIDS (an inhibitor of Clsup-/sup/HCOsub3/subsup-/sup exchangers; i.e., anion exchanger (AE) and Na+-driven Clsup-/sup/HCOsub3/subsup-/sup exchanger (NDCBE)) reduced pHsubc/sub, suggesting that DIDS-sensitive Clsup-/sup/HCOsub3/subsup-/sup transporters such as AE and/or NDCBE keep pHsubc/sub normal by stimulating HCOsub3/subsup-/sup uptake coupled with Clsup-/sup release under an NHE-inhibited condition. EIPA-induced lowered [Clsup-/sup]subc/sub up-regulated expression of p21associated with phosphorylation of MAPKs, suppressing proliferation associated with G₀/Gsub1/sub arrest. biConclusions/i/bbi /i/bEIPA suppressed proliferation of MKN28 cells through up-regulation of p21 expression via reduction of [Clsup-/sup]subc/sub as a result from DIDS-sensitive Clsup-/sup/HCOsub3/subsup-/sup exchanger-mediated compensation for keeping pHsubc/sub normal under an NHE-inhibited condition. This is the first study revealing that an NHE inhibitor suppressed the proliferation of cancer cells by reducing [Clsup-/sup]subc/sub but not pHsubc/sub.
机译：背景/目的 肿瘤细胞由于其高代谢条件而产生大量酸性代谢产物。但是，肿瘤细胞的胞质pH（pH c ）与正常细胞相同，甚至略高于正常细胞。为了将pH c 维持在正常水平或更高水平，肿瘤细胞必须具有比正常细胞更高的H + 转运系统的表达和/或活性。本研究的目的是确定乙基异丙基阿米洛利（EIPA，Na + / H + 交换剂（NHE）的抑制剂）对人胃的增殖的影响癌细胞MKN28。 方法 EIPA对增殖，pH c ，[Cl -] c 的影响在暴露于EIPA 48h的表达NHE的MKN28中研究了调控细胞周期和MAPKs蛋白的表达。 结果 EIPA通过引起G＆＃8320; / G 1 阻滞而抑制MKN28细胞增殖，而对pH c没有明显影响，但与[Cl -] c 的减少有关。尽管仅EIPA对pH c 没有影响，但EIPA与DIDS（Cl - / HCO 3 - 交换剂;即阴离子交换剂（AE）和Na +驱动的Cl - / HCO 3 -交换剂（NDCBE）） pH c ，表明对DIDS敏感的Cl - / HCO 3 -转运蛋白，例如AE和/或NDCBE在NHE抑制条件下，通过刺激HCO 3 -吸收和Cl -释放来保持pH c 正常。 EIPA诱导的p21的[Cl -] c 降低表达与MAPKs磷酸化相关，从而抑制与G＆＃8320; / G 1 相关的增殖子>逮捕。 结论 EIPA通过降低[Cl ]通过上调p21表达来抑制MKN28细胞的增殖。 -] c 来自对DIDS敏感的Cl - / HCO 3 -交换器-介导的补偿，可在NHE抑制条件下保持pH c 正常。这是第一项揭示NHE抑制剂通过降低[Cl -] c 而不是pH c 抑制癌细胞增殖的研究。

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