Deletion of caveolin scaffolding domain alters cancer cell migration
Deletion of caveolin scaffolding domain alters cancer cell migration
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DOI：
10.1080/15384101.2019.1618118
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发表时间：
2019-05-23
期刊：
影响因子：
4.3
通讯作者：
Patel, Hemal H.
中科院分区：
文献类型：
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作者：
Okada, Sunaho;Raja, Sadaf A.;Patel, Hemal H.
小窝蛋白-1(Cav-1)是一种完整的膜蛋白，在细胞增殖和终末分化过程中发挥重要作用。作为小凹病毒的结构成分，Cav-1通过小窝蛋白支架结构域(CSD)与信号分子相互作用，调节细胞信号传导。最近的研究表明，Cav-1在肿瘤转移中是一种负调控因子。因此，我们假设Cav-1通过其CSD抑制细胞迁移。将HeLa细胞过表达Cav-1(Cav-1 OE)、不含功能性CSD(增强型CSD)或增强型绿色荧光蛋白(EGFP)的Cav-1作为对照。在Cav-1 OE细胞中，HeLa细胞的迁移受到抑制，而增加的CSD则表现为迁移增加，这与紧密连接蛋白ZO-1的减少相对应。在多种癌细胞系中证实了这种迁移表型。与对照组相比，Cav-1 OE细胞中磷酸化的STAT-3表达减少，CSD细胞的磷酸化STAT-3表达增加；单独减少STAT-3的表达会减少细胞的迁移。增加CSD通过增加处于细胞周期G2/M期的细胞数量来钝化HeLa的增殖。单独过表达CSD多肽可抑制HeLa细胞的迁移，并抑制pSTAT3。这些发现表明，Cav-1 CSD可能通过促进特定信号转导途径的相互作用、调节STAT3和参与G2/M检查点而在控制癌细胞的动态表型中起关键作用。调节CSD和靶向特定蛋白可能为治疗癌症转移提供潜在的新疗法。
Caveolin-1 (Cav-1) is an integral membrane protein that plays an important role in proliferative and terminally differentiated cells. As a structural component of Caveolae, Cav-1 interacts with signaling molecules via a caveolin scaffolding domain (CSD) regulating cell signaling. Recent reports have shown that Cav-1 is a negative regulator in tumor metastasis. Therefore, we hypothesize that Cav-1 inhibits cell migration through its CSD. HeLa cells were engineered to overexpress Cav-1 (Cav-1 OE), Cav-1 without a functional CSD ( increment CSD), or enhanced green fluorescent protein (EGFP) as a control. HeLa cell migration was suppressed in Cav-1 OE cells while increment CSD showed increased migration, which corresponded to a decrease in the tight junction protein, zonula occludens (ZO-1). The migration phenotype was confirmed in multiple cancer cell lines. Phosphorylated STAT-3 was decreased in Cav-1 OE cells compared to control and increment CSD cells; reducing STAT-3 expression alone decreased cell migration. increment CSD blunted HeLa proliferation by increasing the number of cells in the G2/M phase of the cell cycle. Overexpressing the CSD peptide alone suppressed HeLa cell migration and inhibited pSTAT3. These findings suggest that Cav-1 CSD may be critical in controlling the dynamic phenotype of cancer cells by facilitating the interaction of specific signal transduction pathways, regulating STAT3 and participating in a G2/M checkpoint. Modulating the CSD and targeting specific proteins may offer potential new therapies in the treatment of cancer metastasis.