title: 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: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
authors: Pamela
authors: P
authors: Austin
authors: Spencer A
authors: SA
authors: Freeman
authors: Christopher A
authors: CA
authors: Gray
authors: Michael R
authors: MR
authors: Gold
authors: A Wayne
authors: AW
authors: Vogl
authors: Raymond J
authors: RJ
authors: Andersen
authors: Michel
authors: M
authors: Roberge
authors: Calvin D
authors: CD
authors: Roskelley
mesh_terms: D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects; D009361:Neoplasm Invasiveness; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000199:Actins; D015820:Cadherins; D015815:Cell Adhesion Molecules; D006027:Glycosides; D014315:Triterpenes; C056083:sarasinoside A1