The invasion inhibitor sarasinoside A1 reverses mesenchymal tumor transformation in an E-cadherin-independent manner.

Abstract

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 β-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.

• Authors: Pamela Austin, Spencer A Freeman, Christopher A Gray, Michael R Gold, A Wayne Vogl, Raymond J Andersen, Michel Roberge, Calvin D Roskelley
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 5 Pg. 530-40 (May 2013) ISSN: 1557-3125 [Electronic] United States
• PMID: 23399642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Actins
• Cadherins
• Cell Adhesion Molecules
• Glycosides
• Triterpenes
• sarasinoside A1

Topics

• Actins (metabolism)
• Breast Neoplasms (drug therapy, pathology)
• Cadherins (metabolism)
• Cell Adhesion Molecules (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Glycosides (chemistry, isolation & purification, pharmacology)
• Humans
• Intercellular Junctions (drug effects)
• Neoplasm Invasiveness
• Triterpenes (chemistry, isolation & purification, pharmacology)
• Tumor Cells, Cultured