Cyclooxygenase-2 is an essential mediator of gonadotropins-induced apoptosis of human ovarian surface epithelial cells

Abstract

Objective: To investigate the signaling mechanism underlying gonadotropins-mediated apoptosis of human ovarian surface epithelial (OSE) cells. Methods: OSE cells were treated with surge concentrations of gonadotropins (FSH and LH/hCG), membrane, cytosolic, and nuclear fractions were prepared by differential centrifugation. Expression of N-cadherin, b-catenin, and cyclooxygnease-2 (COX-2) were examined by immunoblot analysis. b-catenin/T-cell factor (TCF) transcriptional activity was measured in a luiferase reporter gene assay. Results: We demonstrated that disruption of N-cadherin-mediated cell-cell adhesion by gonadotropins is an important molecular event in the apoptosis in human OSE. This downregulation of N-cadherin was correlated with a redistribution of b-catenin from the plasma membrane to the nucleus, resulting in the activation of b-catenin/T Cell Factor (TCF) transcription. These events were mediated via a phosphatidylinositol 3-kinase (PI3K)-dependent phosphorylation of the inhibitory serine 9 residue of glycogen synthase kinase-3b (GSK3-b). In addition, we showed that COX-2, a target of b-catenin/TCF, is an important mediator of the gonadotropins-induced apoptosis of OSE. Conclusion: These findings shed new light on the molecular mechanism underlying OSE survival and death, a process that is anticipated to have important implication in the ovulation and ovarian cancer risk.