NaV1.5 Na+ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia
NaV1.5 Na+ channels allosterically regulate the NHE-1 exchanger and promote the activity of breast cancer cell invadopodia
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DOI：
10.1242/jcs.123901
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发表时间：
2013-11-01
影响因子：
4
通讯作者：
Roger, Sebastien
中科院分区：
文献类型：
--
作者：
Brisson, Lucie;Driffort, Virginie;Roger, Sebastien
癌细胞对细胞外基质的降解是肿瘤转移过程中必不可少的一步，这是由称为内陷的癌细胞结构完成的。Na(V)1.5(也称为SCN5A)Na+通道在乳腺癌中过度表达，并与转移的发生有关。已有研究表明，Na(V)1.5活性通过膜周酸化和半胱氨酸组织蛋白降解细胞外基质来增强乳腺癌细胞的侵袭性。在这里，我们发现NaV1.5与Na+/H+交换器类型1(NHE-1)和小窝蛋白-1在MDA-MB-231乳腺癌细胞的侵入性足部的基质重塑位置上是共定位的。NHE-1、Na(V)1.5和小窝蛋白-1免疫共沉淀，表明这些蛋白之间存在密切的联系。我们发现，Na(V)1.5的表达与NHE-1的变构调节有关，使其在细胞内pH 6.4-7的范围内更具活性；因此，它可能向细胞外空间挤出更多的质子。此外，Na(V)1.5的表达增加了Src激酶活性和肌动蛋白成核促进因子Cortactin的磷酸化(Y421)，改变了F-肌动蛋白的聚合，并促进了这些细胞获得侵袭性形态。综上所述，我们的研究表明，Na(V)1.5是乳腺癌细胞中内陷形成和活性的中心调节因子。
The degradation of the extracellular matrix by cancer cells represents an essential step in metastatic progression and this is performed by cancer cell structures called invadopodia. Na(V)1.5 (also known as SCN5A) Na+ channels are overexpressed in breast cancer tumours and are associated with metastatic occurrence. It has been previously shown that Na(V)1.5 activity enhances breast cancer cell invasiveness through perimembrane acidification and subsequent degradation of the extracellular matrix by cysteine cathepsins. Here, we show that NaV1.5 colocalises with Na+/H+ exchanger type 1 (NHE-1) and caveolin-1 at the sites of matrix remodelling in invadopodia of MDA-MB-231 breast cancer cells. NHE-1, Na(V)1.5 and caveolin-1 co-immunoprecipitated, which indicates a close association between these proteins. We found that the expression of Na(V)1.5 was responsible for the allosteric modulation of NHE-1, rendering it more active at the intracellular pH range of 6.4-7; thus, it potentially extrudes more protons into the extracellular space. Furthermore, Na(V)1.5 expression increased Src kinase activity and the phosphorylation (Y421) of the actin-nucleation-promoting factor cortactin, modified F-actin polymerisation and promoted the acquisition of an invasive morphology in these cells. Taken together, our study suggests that Na(V)1.5 is a central regulator of invadopodia formation and activity in breast cancer cells.