Selective inhibition of prostaglandin E 2 signaling inhibits migration and invasion of human endometriotic epithelial and stromal cells through multiple mechanisms

Abstract

OBJECTIVE: Prostaglandin E2 (PGE2) plays central role in the pathogenesis of endometriosis. We have shown that selective inhibition of COX-2 prevents survival, migration, and invasion (Endocrinology, 2008), and inhibition of EP2 and EP4 induces apoptosis (Molecular Endocrinology, 2009) of human endometriotic epithelial and stromal cells. In this study, we determined molecular association between PGE2 signaling and migration and invasion potential of human endometriotic cells. DESIGN: Human endometriotic and endometrial tissues from proliferative phase of the menstrual cycle and human immortalized endometriotic epithelial cells 12Z and stromal cells 22B. MATERIALS AND METHODS: Spatial expression of PGE2 receptors EP1, EP2, EP3 and EP4 were studied in human ectopic (n=12) and eutopic endometria (n=12) using immunohistochemistry. PGE2 signaling was inhibited using pharmacological and genomic approaches in endometriotic epithelial cells 12Z and stromal cells 22B, and their effects on migration and invasion of endometriotic cells and the underlined molecular mechanisms were determined (n=3). RESULTS: Our data indicated that EP2 and EP4 were highly (P<0.05) expressed in glandular epithelium and stoma of ectopic compared to eutopic endometria. EP1 was expressed at very low level in both ectopic and eutopic endometria. EP3 was undetectable in both endometria. Selective inhibition of EP2 and EP4 receptors inhibited (P<0.05) migration and invasion of endometriotic epithelial cells 12Z and stromal cells 22B in a cell-specific manner. This effect was mediated through inhibition of metalloproteinases MMP2 and MMP9 activities via suppression of ERK1/2, AKT, NFkB and b-catenin pathways. CONCLUSIONS: Our results suggest that selective inhibition of EP2 and EP4 could be used as novel non-estrogen hormonal therapy for endometriosis, pending in vivo studies.