The Invasion Inhibitor Sarasinoside A1 Reverses Mesenchymal Tumor Transformation in an E-Cadherin-Independent Manner
The Invasion Inhibitor Sarasinoside A1 Reverses Mesenchymal Tumor Transformation in an E-Cadherin-Independent Manner
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DOI：
10.1158/1541-7786.mcr-12-0385
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发表时间：
2013-05-01
影响因子：
5.2
通讯作者：
Roskelley, Calvin D.
中科院分区：
文献类型：
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作者：
Austin, Pamela;Freeman, Spencer A.;Roskelley, Calvin D.
在转移进展期间，最常由细胞-细胞粘附分子E-钙粘蛋白的丢失驱动的异常上皮-间充质转化（EMT）产生高度侵袭性的非粘性肿瘤细胞。我们使用间充质转化的，E-钙粘蛋白阴性的MDA-MB-231乳腺癌细胞在天然产物筛选和确定，三萜皂苷sarasinoside A1抑制他们的入侵和入侵的一些其他肿瘤细胞系。Sarasinoside A1还导致MDA-MB-231细胞在三维基底膜和胶原凝胶培养物中变得粘着。在二维培养中，sarasinoside A1启动了MDA-MB-231细胞的形态再上皮化，其中预先存在的非上皮钙粘蛋白和连接相关蛋白β-连环蛋白和ZO-1都重新定位到细胞-细胞接触的位点。此外，相邻细胞之间的细胞间隙大大缩小，在细胞-细胞接触部位的聚合肌动蛋白的稳定性增加，并有一个招聘和稳定的基于连接蛋白的粘附复合物，这些网站，所有这些都强烈表明，功能性细胞-细胞连接已经形成。重要的是，sarasinoside A1诱导新生细胞-细胞连接的形成，不需要基因表达的变化，并不与诱导的E-钙粘蛋白，但导致增加激活的RAP GTP酶。因此，我们的研究结果与sarasinoside A1表明，它可能是可能的再上皮化转移性肿瘤细胞的表型结果，甚至当E-钙粘蛋白是完全缺乏。（C）2013年AACR。
During metastatic progression, an aberrant epithelial-to-mesenchymal transformation (EMT) that is most often driven by the loss of the cell-cell adhesion molecule E-cadherin generates noncohesive tumor cells that are highly invasive. We used mesenchymally transformed, E-cadherin-negative MDA-MB-231 breast carcinoma cells in a natural product screen and determined that the triterpenoid saponin sarasinoside A1 inhibited their invasion and the invasion of a number of other tumor cell lines. Sarasinoside A1 also caused MDA-MB-231 cells to become cohesive in a three-dimensional basement membrane and collagen gel cultures. In two-dimensional culture, sarasinoside A1 initiated a morphologic re-epithelialization of MDA-MB-231 cells wherein preexisting nonepithelial cadherins and the junction-associated proteins beta-catenin and ZO-1 all relocalized to sites of cell-cell contact. In addition, the intercellular space between neighboring cells narrowed considerably, the stability of polymerized actin at cell-cell contact sites increased, and there was a recruitment and stabilization of nectin-based adhesion complexes to these sites, all of which strongly suggested that functional cell-cell junctions had formed. Importantly, sarasinoside A1 induced nascent cell-cell junction formation that did not require changes in gene expression and was not associated with an induction of E-cadherin but resulted in increased activation of Rap GTPases. Therefore, our findings with sarasinoside A1 suggest that it may be possible to re-epithelialize metastatic tumor cells with phenotypic consequence even when E-cadherin is completely absent. (C)2013 AACR.