title: Gonadotropin-induced apoptosis in human ovarian surface epithelial cells is associated with cyclooxygenase-2 up-regulation via the beta-catenin/T-cell factor signaling pathway.
abstract: 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-3beta 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-3beta. 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.
authors.affiliation: Department of Zoology, University of Hong Kong, Pokfulam Road, Hong Kong.
authors.forename: Yuen Lam
authors.initials: YL
authors.lastname: Pon
authors.forename: Alice S T
authors.initials: AS
authors.lastname: Wong
mesh_terms: D017209:Apoptosis; D002448:Cell Adhesion; D051546:Cyclooxygenase 2 / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006062:Gonadotropins / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D010053:Ovary / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D051176:beta Catenin / Q000819:agonists / Q000235:genetics / Q000502:physiology*
chemical_list: D006062:Gonadotropins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha