sphingosine-1-phosphate and Ascites

Epithelial ovarian cancer (EOC) arises from the epithelial layer covering the surface of ovaries and i.p. metastasis is commonly observed at diagnosis. Sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule, is potentially involved in EOC tumorigenesis. We have found that S1P is elevated in human EOC ascites. We show that physiologically relevant concentrations of S1P stimulate migration and invasion of EOC cells but inhibit migration of human ovarian surface epithelial (HOSE) cells. In addition, S1P inhibits lysophosphatidic acid (LPA)-induced cell migration in HOSE but not in EOC cells. We have provided the first line of evidence that the expression levels of S1P receptor subtypes are not the only determinants for how cells respond to S1P. Although S1P(1) is expressed and functional in HOSE cells, the inhibitory effect mediated by S1P(2) is dominant in those cells. The cellular preexisting stress fibers are also important determinants for the migratory response to S1P. Differential S1P-induced morphology changes are noted in EOC and HOSE cells. Preexisting stress fibers in HOSE cells are further enhanced by S1P treatment, resulting in the negative migratory response to S1P. By contrast, EOC cells lost stress fibers and S1P treatment induces filopodium-like structures at cell edges, which correlates with increased cell motility. In addition, inhibition of the protein kinase C pathway is likely to be involved in the inhibitory effect of S1P on LPA-induced cell migration in HOSE cells. These findings are important for the development of new therapeutics targeting S1P and LPA in EOC.

Topics: Ascites; Cell Line, Tumor; Cell Movement; Cell Shape; Enzyme Activation; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Lysophospholipids; Mitogen-Activated Protein Kinase Kinases; Ovarian Neoplasms; Protein Kinase C; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Stress Fibers

Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule. It stimulates the growth of some cells, but inhibits the growth of others. In this study, we describe the detection of sub-microM to microM concentrations of S1P in the ascitic fluids of patients with ovarian cancer. In ovarian cancer cells cultured in vitro, S1P exhibited a dual effect on growth and/or survival. S1P (10 microM) induced cell death when cells were in suspension but stimulated cell growth when cells were attached. The calcium-dependent induction of cell death by S1P is apparently associated with its inhibitory effect on cell attachment and cell adhesion. S1P (10-30 microM) also induced calcium-dependent cell-cell aggregation.

Topics: Ascites; Cell Adhesion; Cell Aggregation; Cell Death; Cell Division; Female; Humans; Lysophospholipids; Ovarian Neoplasms; Sphingosine; Tumor Cells, Cultured