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Gonadotropin-Induced Apoptosis in Human Ovarian Surface Epithelial Cells Is Associated with Cyclooxygenase-2 Up-Regulation via the ß-Catenin/T-Cell Factor Signaling Pathway

Department of Zoology, University of Hong Kong, Hong Kong

Address all correspondence and requests for reprints to: Alice S. T. Wong, 4S-14 Kadoorie Biological Sciences Building, Department of Zoology, University of Hong Kong, Pokfulam Road, Hong Kong. E-mail: awong1{at}hku.hk

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 ß-catenin/T-cell factor (TCF) signaling by gonadotropins. We further showed that ectopic expression of N-cadherin was sufficient to recruit ß-catenin to the plasma membrane, thereby blocking ß-catenin/TCF-mediated transactivation in gonadotropin-treated cells. Transfection with ß-catenin small interfering RNA or expression of dominant negative TCF inhibited apoptosis, whereas expression of dominant stable ß-catenin (S37A) caused significant apoptosis, thus supporting a proapoptotic role for ß-catenin/TCF in human OSE. In addition, we showed that gonadotropins enhanced ß-catenin/TCF transcriptional activity through inactivation of glycogen synthase kinase-3ß in a phosphatidylinositol 3-kinase/Akt-dependent manner, indicating cross talk between the phosphatidylinositol 3-kinase/Akt and ß-catenin signaling pathways through glycogen synthase kinase-3ß. Furthermore, gonadotropins increased cyclooxygenase-2 (COX-2) expression via the ß-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 ß-catenin in adhesion and signaling may represent a novel mechanism through which gonadotropins may regulate the cellular fate of human OSE.

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				J.-H. Choi, A. S. T. Wong, H.-F. Huang, and P. C. K. Leung Gonadotropins and Ovarian Cancer Endocr. Rev., June 1, 2007; 28(4): 440 - 461. [Abstract] [Full Text] [PDF]