Gonadotropin-induced apoptosis in human ovarian surface epithelial cells is associated with cyclooxygenase-2 up-regulation via the β-catenin/T-cell factor signaling pathway

Gonadotropins play a prominent role in ovarian function and pathology. We have shown that treatment with gonadotropins (FSH and LH/human chorionic gonadotropin) reduces the amount of N-cadherin with a concomitant induction of apoptosis in human ovarian surface epithelial (OSE) cells, but precise molecular mechanisms remain to be elucidated. Here, we demonstrated activation of beta-catenin/T-cell factor (TCF) signaling by gonadotropins. We further showed that ectopic expression of N-cadherin was sufficient to recruit beta-catenin to the plasma membrane, thereby blocking beta-catenin/TCF-mediated transactivation in gonadotropin-treated cells. Transfection with beta-catenin small interfering RNA or expression of dominant negative TCF inhibited apoptosis, whereas expression of dominant stable beta-catenin (S37A) caused significant apoptosis, thus supporting a proapoptotic role for beta-catenin/ TCF in human OSE. In addition, we showed that gonadotropins enhanced beta-catenin/ TCF transcriptional activity through inactivation of glycogen synthase kinase-3 beta in a phosphatidylinositol 3-kinase/Akt-dependent manner, indicating cross talk between the phosphatidylinositol 3-kinase/Akt and beta-catenin signaling pathways through glycogen synthase kinase-3 beta. Furthermore, gonadotropins increased cyclooxygenase-2 (COX-2) expression via the beta-catenin/ TCF pathway. COX-2 also played a role in gonadotropin-induced apoptosis, as treatment with the COX-2-specific inhibitor NS-398 or COX-2 small interfering RNA blocked gonadotropin-dependent apoptotic activity. These findings suggest that the participation of beta-catenin in adhesion and signaling may represent a novel mechanism through which gonadotropins may regulate the cellular fate of human OSE.