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

Mol Endocrinol. 2006 Dec;20(12):3336-50. doi: 10.1210/me.2006-0125. Epub 2006 Aug 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Cell Adhesion
  • Cyclooxygenase 2 / physiology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Female
  • Glycogen Synthase Kinase 3 / metabolism
  • Gonadotropins / pharmacology*
  • Humans
  • Membrane Proteins / agonists
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / physiology*
  • Ovary / cytology
  • Ovary / drug effects*
  • Ovary / enzymology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Signal Transduction
  • TCF Transcription Factors / agonists
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / physiology*
  • Transcription, Genetic / drug effects
  • Up-Regulation
  • beta Catenin / agonists
  • beta Catenin / genetics
  • beta Catenin / physiology*

Substances

  • Gonadotropins
  • Membrane Proteins
  • RNA, Small Interfering
  • TCF Transcription Factors
  • beta Catenin
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha