Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells

Lysophosphatidic acid (LPA) is present at high concentrations in ascites fr om ovarian cancer patients and has potent mitogenic properties in vitro. Ur okinase plasminogen activator (uPA), a critical component of the metastatic cascade, Is also found at high concentrations in ovarian ascites and ovari an cancers, and the levels of uPA correlate inversely with prognosis, Becau se LPA stimulates the invasion of both hepatoma and lung cell lines, we inv estigated whether LPA could induce uPA secretion by ovarian epithelial cell s and whether this process was associated with malignant transformation of ovarian epithelial cells. As indicated by zymography and Western blotting, physiologically relevant concentrations of LPA equivalent to those present in ovarian cancer ascites stimulated uPA secretion in the ovarian cancer ce ll lines OVCAR-3, SKOV-3, OVCA 429, OVCA 432, and OVCA 433, but not from es tablished normal ovarian epithelial (NOE) cells as indicated by normal epit helial cell lines NOE 033 and NOE 035 or from SV40 large T antigen-immortal ized normal epithelial cell lines IOSE 29 and IOSE 80, 18:1 LPA, but not 18 :0 LPA, 16:0 LPA, or lysophosphatidylcholine, induced uPA secretion, concor dant with previous studies of LPA receptor selectivity. Expression of the e dg-2 LPA receptor was not consistently different between normal epithelial cell lines and ovarian cancer cell lines. In contrast, expression of the ed g-4 LPA receptor was markedly increased in ovarian cancer cell lines as com pared with NOE cell lines, raising the possibility that the edg-4 LPA recep tor contributes to the ability of ovarian cancer cells but not NOE cells to produce uPA in response to LPA, LPA induced a consistent increase in uPA p romoter activity and mRNA Levels, suggesting that increased uPA production is, at least in part, transcriptional. Malignant transformation may alter L PA-induced cell activation by altering the pattern of LPA receptors present and may possibly lead to more aggressive behavior by up-regulating LPA-med iated uPA secretion and stimulating extracellular stromal breakdown and inv asion.