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Endothelin-1 enhances proliferation of lung cancer cells by increasing intracellular free Ca2+

机译：内皮素-1通过增加细胞内游离钙离子来增强肺癌细胞的增殖

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摘要

Endothelin-1 (ET-1), the most potent vasoconstrictor, has been shown to be mitogenic in many tumor cells as well as in vascular cells. It was previously reported that the mRNA of ET-1 and endothelin receptors (ETRs) are expressed in lung cancer cells. However, their biological role in lung cancer remains to be explored. The purpose of this study was to determine whether ET-1 stimulates proliferation of the human lung adenocarcinoma cell SPC-A1 and probe its cellular mechanism. Reverse-transcription polymerase chain reaction and Western blot analysis showed that both the mRNA and protein of ET-1, ETAR and ETBR are expressed in SPC-A1 cells. Application of ET-1 at 10(-15)-10(-8) M caused a dose-dependent cell proliferation and an increase in intracellular free Ca2+ concentration ([Ca2+](i)). This ET-1-induced cell proliferation and [Ca2+](i) increase were completely abolished by BQ123, a selective ETAR antagonist, but not by BQ788, a selective ETBR antagonist. Furthermore, it was significantly reduced by U73122, a specific inhibitor of phospholipase C (PLC), but not by U73433, the structural isomer of U73122. Chelating extracellular Ca2+ or blocking voltage dependent calcium channels by nifedipine also significantly reduced the mitogenic effect of ET-1 and [Ca2+] i increase in SPC-A1 cells. These results indicate that ET-1 acts as an autocrine growth factor and enhances proliferation of SPC-Al cells via activation of ETAR. The phosphomositol/Ca2+ pathway and Ca2+ influx through voltage dependent Ca2+ channels activated by ETAR contribute to this process. (c) 2008 Elsevier Inc. All rights reserved.
机译：内皮素-1（ET-1）是最有效的血管收缩剂，在许多肿瘤细胞以及血管细胞中均显示出促有丝分裂作用。以前有报道说，ET-1和内皮素受体（ETR）的mRNA在肺癌细胞中表达。然而，它们在肺癌中的生物学作用仍有待探索。这项研究的目的是确定ET-1是否刺激人肺腺癌细胞SPC-A1的增殖并探究其细胞机制。逆转录聚合酶链反应和蛋白质印迹分析表明，ET-1，ETAR和ETBR的mRNA和蛋白均在SPC-A1细胞中表达。在10（-15）-10（-8）M处应用ET-1导致剂量依赖性细胞增殖，并增加细胞内游离Ca2 +浓度（[Ca2 +]（i））。选择性ETAR拮抗剂BQ123完全消除了ET-1诱导的细胞增殖和[Ca2 +]（i）的增加，但是选择性ETBR拮抗剂BQ788则没有。此外，它被磷脂酶C（PLC）的特异性抑制剂U73122显着降低，但未被U73122的结构异构体U73433降低。硝苯地平螯合细胞外Ca2 +或阻断电压依赖性钙通道也显着降低了SPC-A1细胞中ET-1和[Ca2 +] i的促有丝分裂作用。这些结果表明，ET-1起自分泌生长因子的作用，并通过激活ETAR增强SPC-A1细胞的增殖。磷酸肌醇/ Ca2 +途径和通过ETAR激活的电压依赖性Ca2 +通道的Ca2 +流入有助于此过程。 （c）2008 Elsevier Inc.保留所有权利。

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