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In the Western world, endometrial cancer is the most common gynecologic cancer and is the fourth importance among all feminine cancers. Cyclooxygenase-1 and -2 (COX-1 and -2) are the limiting enzyme that catalyzes the synthesis of prostaglandins (PGs) from arachidonic acid. The PGs have been shown to be implicated in evolution and tumor transformation, particularly, PGE2. Four prostaglandin E2 receptors have been found: EP1, EP2, EP3 and EP4. The aim of this study was to determine if resveratrol, a natural anti-oxidant found in red wine, could influence the production of PGs and apoptotic cell death or cellular proliferation. Six different human uterine cancer cell lines were used for this study. Real-time RT-PCR and Western analyses were carried out to measure COX-1, COX-2, EP1, EP2, EP3 and EP4 expression. The results indicated that all cell lines expressed both COX isoforms and the four EP receptors at different levels. In experiment two, cells were treated with various concentrations of resveratrol for different length of time. MTT proliferation assay revealed that resveratrol induced maximal cell proliferation of RL-95-2 cells in a dose dependent manner after 24 hours, which was reduced after 48 and 72 hours. Resveratrol had no effect on KLE cells in term of proliferation but inhibited cell proliferation in HeLa and HEC-1-A in a dose and time dependant manner. In Ishikawa and TOV-1078D cells, a novel human endometrial cancer cell line, the effect of resveratrol was biphasic: cell proliferation was increased at low concentration whereas higher concentrations resulted in a decreased of cell proliferation in a time dependent manner. Hoechst nuclear staining indicated that resveratrol induced apoptosis in HeLa, HEC-1-A, Ishikawa and TOV-1078D but not in KLE and RL-95-2 cells. Since we have showed that Akt activity can directly up-regulate COX-2 gene expression and PGE2 secretion, in experiment two Western blot analyses were carried out to determine the possible involvement of the PI3-K/PTEN/Akt pathway in this process. Results indicate that, depending on the cell line, resveratrol can act positively and negatively on Akt phosphorylation in those wild types (HeLa, HEC-1-A and KLE) and mutated PTEN (RL-95-2, Ishikawa and TOV-1078D) human uterine cancer cells and that COX-1 and COX-2 expressions are influenced by resveratrol. In response to resveratrol PGE2 secretion was decreased in HeLa, HEC-1-A and Ishikawa cells. The results suggest that resveratrol, through its action on prostaglandin biosynthesis, could be an important regulator of cell survival in uterine cancer. Supported by CIHR (MOP-66987).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]