title: Gonadotropins induce tumor cell migration and invasion by increasing cyclooxygenases expression and prostaglandin E(2) production in human ovarian cancer cells.
abstract: 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 PGE(2) 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of British Columbia, 2H30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5.
authors.forename: Man-Tat
authors.initials: MT
authors.lastname: Lau
authors.forename: Alice S T
authors.initials: AS
authors.lastname: Wong
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006062:Gonadotropins / Q000494:pharmacology*; D006801:Humans; D007986:Luteinizing Hormone / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006062:Gonadotropins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone