Alkyl-lysophospholipid 1-O-octadecyl-2-O-methyl-glycerophosphocholine induces invasion through epislalin-mediated neutralization of E-cadherin in human mammary MCF-7 cells in vitro

1-O-octadecyl-2-O-methyl-glycerophosphocholine (ET-18-OMe) is an analogue o f the naturally occurring 2-lysophosphatidylcholine belonging to the class of antitumor lipids. Previously, we demonstrated that ET-18-OMe modulates c ell-cell adhesion of human breast cancer MCF-T cells. In the present study, we tested the effect of ET-18-OMe on adhesion, invasion and localisation o f episialin and E-cadherin in MCF-7/AZ cells expressing a functional E-cadh erin/catenin complex, The MCF-7/6 human breast cancer cells were used as ne gative control since their E-cadherin/catenin complex is functional in cell s grown on solid substrate but not in suspension. The function of E-cadheri n, a calcium-dependent transmembrane cell-cell adhesion and signal-transduc ing molecule, is disturbed in invasive cancers by mutation, loss of mRNA st ability, proteolytic degradation, tyrosine phosphorylation of associated pr oteins and large cell-associated proteoglycans or mucin-like molecules such as episialin. Episialin, also called MUC1, is an anti-adhesion molecule th at by its large number of glycosylated tandem repeats can sterically hinder the adhesive properties of other glycoproteins. ET-18-OMe inhibited the E- cadherin functions of MCF-7/AZ cells as measured by inhibition of fast and slow aggregation and by the induction of collagen invasion. These effects w ere enhanced by MB2, an antibody against E-cadherin and blocked by monoclon al antibodies (MAbs) 214D4 or M8 against episialin, ET-18-OMe had no influe nce on tyrosine phosphorylation of beta -catenin and the E-cadherin/catenin complex remained intact. Transcription, translation, protein turnover and cell surface localisation of episialin were not altered. ET-18-OMe induced finger-like extensions with clustering of episialin together with E-cadheri n and carcinoembryonic antigen but not with occludin. In cells in suspensio n, ET-18-OMe caused a shift in the flow-cytometric profile of episialin tow ard a lower intensity for MCF-7/AZ cells. In contrast with MCF-7/AZ cells, the adhesion-deficient and noninvasive MCF-7/6 cells showed neither morphot ypic changes nor induction of aggregation nor invasion in collagen I upon t reatment with ET-18-OMe, Co-localisation of episialin with E-cadherin was r arely observed, We conclude that in the human breast cancer cells MCF-7/AZ, E-cadherin and episialin are key molecular players in the regulation of pr omotion and suppression of cell-cell adhesion and invasion. (C) 2001 Wiley- Liss, Inc.