STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization
STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization
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DOI：
10.1074/jbc.m114.598425
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发表时间：
2015-05-08
影响因子：
4.8
通讯作者：
Wygrecka, Malgorzata
中科院分区：
文献类型：
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作者：
Didiasova, Miroslava;Zakrzewicz, Dariusz;Wygrecka, Malgorzata
背景：细胞表面相关烯醇化酶-1调节纤溶酶的形成，从而调节细胞周围的蛋白水解。结果：STIM 1/ORAI 1介导的Ca 2+内流控制了癌细胞中烯醇化酶-1的外化。结论：细胞外烯醇化酶-1调节癌细胞的迁移和侵袭特性。重要性：增强的烯醇化酶-1外源化可加重癌细胞的恶性行为，从而促进转移的形成，肿瘤细胞利用纤溶酶的广谱蛋白水解活性侵入组织并形成转移灶。细胞表面相关烯醇化酶-1（ENO-1）促进纤溶酶的形成，从而参与细胞周围蛋白水解的调节。尽管在不同类型的癌症中已经描述了细胞表面结合的ENO-1水平的增加，但负责ENO-1外化的分子机制仍然难以捉摸。在本研究中，在乳腺导管癌和高转移性乳腺癌细胞系MDA-MB-231的细胞表面发现ENO-1蛋白水平增加。细胞表面相关的ENO-1表达升高与MDA-MB-231细胞迁移和侵袭特性增强相关。MDA-MB-231细胞暴露于LPS增强了ENO-1向细胞表面的易位，并以外泌体的形式释放到细胞外空间。这些影响是独立的从头蛋白质合成，并不需要经典的内质网/高尔基体途径。用钙离子螯合剂BAPTA或内质网Ca ~（2+）-ATP酶泵抑制剂环匹阿尼酸预处理MDA-MB-231细胞可抑制LPS触发的ENO-1外向化。与这些观察结果一致，发现基质相互作用分子（STIM）1和钙释放激活的钙调节剂（奥赖）1介导的钙库操作的Ca 2+内流调节LPS诱导的ENO-1外化。药物阻断或敲低STIM 1或ORAI 1可降低MDA-MB-231细胞的ENO-1依赖性迁移。总的来说，我们的研究结果表明，钙池操作的Ca 2+通道介导的Ca 2+内流的调控ENO-1 exteriorization，从而在调节癌细胞的迁移和侵袭性的关键作用。
Background: Cell surface-associated enolase-1 regulates plasmin formation and thus pericellular proteolysis. Results: STIM1/ORAI1-mediated Ca2+ influx controls enolase-1 exteriorization in cancer cells. Conclusion: Extracellular enolase-1 regulates migratory and invasive properties of cancer cells. Significance: Enhanced exteriorization of enolase-1 may aggravate the malignant behavior of cancer cells and thus contribute to metastasis formation.Tumor cells use broad spectrum proteolytic activity of plasmin to invade tissue and form metastatic foci. Cell surface-associated enolase-1 (ENO-1) enhances plasmin formation and thus participates in the regulation of pericellular proteolysis. Although increased levels of cell surface bound ENO-1 have been described in different types of cancer, the molecular mechanism responsible for ENO-1 exteriorization remains elusive. In the present study, increased ENO-1 protein levels were found in ductal breast carcinoma and on the cell surface of highly metastatic breast cancer cell line MDA-MB-231. Elevated cell surface-associated ENO-1 expression correlated with augmented MDA-MB-231 cell migratory and invasive properties. Exposure of MDA-MB-231 cells to LPS potentiated translocation of ENO-1 to the cell surface and its release into the extracellular space in the form of exosomes. These effects were independent of de novo protein synthesis and did not require the classical endoplasmic reticulum/Golgi pathway. LPS-triggered ENO-1 exteriorization was suppressed by pretreatment of MDA-MB-231 cells with the Ca2+ chelator BAPTA or an inhibitor of endoplasmic reticulum Ca2+-ATPase pump, cyclopiazonic acid. In line with these observations, the stromal interaction molecule (STIM) 1 and the calcium release-activated calcium modulator (ORAI) 1-mediated store-operated Ca2+ entry were found to regulate LPS-induced ENO-1 exteriorization. Pharmacological blockage or knockdown of STIM1 or ORAI1 reduced ENO-1-dependent migration of MDA-MB-231 cells. Collectively, our results demonstrate the pivotal role of store-operated Ca2+ channel-mediated Ca2+ influx in the regulation of ENO-1 exteriorization and thus in the modulation of cancer cell migratory and invasive properties.