Lysophosphatidic acid and sphingosine-1-phosphate activate the Rap1 GTPase and inhibit fibronectin-dependent migration in the MDA-MB231 breast cancer cell line

Proc Amer Assoc Cancer Res, Volume 47, 2006 1817 The extracellular lipid mediators lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are potent regulators of cell migration and cell invasion. Activation of the Rap1 GTPase has also been shown to regulate cell migration. Interestingly, LPA, S1P and Rap1 can all either stimulate or inhibit cell migration/invasion in cell type- and cell context-specific manners. These context-dependent effects on migration and invasion may explain why LPA, S1P, and Rap1 have been reported to either promote or suppress metastatic tumor progression, depending on the system. Here we report that LPA and S1P both stimulate Rap1 activation in the highly metastatic MDA-MB231 breast cancer cell line. LPA and S1P also inhibited MDA-MB231 cell migration and this effect could be modulated by altering cell-substratum adhesion. Specifically, the ability of LPA and S1P to inhibit the migration of MDA-MB231 cells was enhanced when the cells were plated on high concentrations of fibronectin attached to a planar substratum. Thus, altering integrin-mediated adhesion may modulate the phenotypic response of breast tumor cells to lipid mediators. We are currently determining if adhesion-dependent changes in Rap1 activation influence the LPA- and S1P-induced inhibition of migration in these cells. Such studies may reveal novel mechanisms by which lipid mediators, acting perhaps via Rap1, exert pleiotrophic effects on tumor progression. (Supported by grants from the National Cancer Institute of Canada and the Cancer Research Society)