Gonadotropins Induce Tumor Cell Migration and Invasion by Increasing Cyclooxygenases Expression and Prostaglandin E2 Production in Human Ovarian Cancer Cells

Gonadotropins (FSH and LH) are detectable in ovarian tumor fluid, suggesting a possible role for gonadotropins in ovarian carcinogenesis and progression. However, the molecular mechanisms behind the role of gonadotropins in ovarian cancer development are unknown. Cyclooxygenase (COX) enzymes, COX-1 and COX-2, play crucial roles in the pathogenesis of human malignancies. The purpose of the current study was to determine whether the effect of gonadotropins on ovarian cancer invasion is mediated by a COX-dependent mechanism. Here, we reported that FSH/LH can promote prostaglandin E-2 (PGE(2)) production in ovarian cancer cells via COX-1 and -2 up-regulation at the protein and mRNA level. The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway was required for gonadotropin-mediated up-regulation of COX-1 and COX-2. Moreover, treatment with COX-1- and COX-2-specific inhibitors abrogated the stimulatory effect of gonadotropins on motility and invasive activity. Western blot and gelatin zymography showed that COX-1 and COX-2 were critical for gonadotropin-induced expression of metastasis-related proteinases, matrix metalloproteinase (MMP)-2 and MMP-9. In addition, our results showed that PGE2 induced an increase in cell invasiveness and the expression of MMP-2 and MMP-9 in ovarian cancer cells. These data show that COX-1 and COX-2 play essential roles in gonadotropin-induced migration and invasion. (Endocrinology 151: 2985-2993, 2010)