| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 95 === Lysophosphatidic acid (LPA) is a simple phospholipid with diverse actions, including platelet aggregation, smooth muscle contraction, cancer cell invasion and proliferation. The cancer promoting effects of LPA have been extensively studied since a high concentration of LPA was noted in the ascites and plasma of ovarian cancer patients. Numerous studies have shown that LPA is actively secreted by, and induces proliferation and migration in ovarian cancer cells. LPA has been demonstrated to increase ovarian cancer cell migration through stimulating expression of cyclooxygenase-2 (COX-2), an inducible enzyme that catalyzes the rate limiting step in prostaglandin synthesis. COX-2 expression is elevated in many cancers and prostaglandins have been found to activate proliferation and migration in various cancer cell types. The purpose of this study was to clarify whether LPA would promote ovarian cancer cell proliferation through COX-2 induction, and to identify the involving signaling pathways. BrdU incorporation assay was used to analyze cell proliferation. COX-2 promoter fused to a luciferase reporter gene was transiently transfected into cells, and the promoter activation was examined by luciferase assay. Measurements of COX-2 mRNA were also conducted in ovarian cancer cell lines. A COX-2 specific inhibitor NS-398 was used to evaluate the role of COX-2 in ovarian cancer cell proliferation. Current results demonstrate that LPA induces ovarian cancer cell proliferation. LPA also induced COX-2 promoter activation and mRNA expression. Thus, we propose that LPA may stimulate cell proliferation through upregulation of COX-2. COX-2 inhibition dose-dependently reduced cell proliferation, and completely abolished the proliferating effect of LPA at a dose of 100 mM. In order to find the signaling pathway leading to COX-2 expression and cell proliferation, we employed various cell signaling inhibitors on LPA-induced cell proliferation. Inhibition of PI3K with LY294002 and Wortmannin significantly inhibited LPA-induced cell proliferation. Using luciferase assay, PI3K inhibition was also found to reduce LPA-induced COX-2 promoter activity. Thus, LPA may elevate expression of COX-2 via PI3K activation, leading to ovarian cancer cell proliferation. This finding also implicates LPA and COX-2 as putative targets for the treatment of ovarian cancer.
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