Prostaglandin E2 Regulates Survival of Human Endometriotic Epithelial and Stromal Cells by Integrating EGFR, NFkB, and Wnt Signaling Pathways Through EP2 and EP4 Receptors.

Endometriosis is a debilitating disease affects up to 20% of reproductive age women characterized by the presence of functional endometrial glandular epithelium and stroma outside the uterine cavity that results in chronic pelvic pain and infertility. The pathophysiology of endometriosis remains an enigma in reproductive medicine. Available treatment options are very limited which include oral contraceptives, aromatase inhibitors and gonadotropin releasing hormone analogues, and surgical removal of uterus with or without ovaries. All these treatments compromise fertility and reproductive health in women. Accumulating evidence indicates that steroids, growth factors, cytokines and prostaglandins promote establishment and maintenance of endometriosis. Prostaglandin E2 (PGE2) promotes cell proliferation, migration, invasion, angiogenesis, anti-apoptosis, pain and immunomodulation. Biosynthesis of PGE2 is rate limited by enzyme cyclooxygenase-2 (COX-2). Effects of PGE2 are primarily mediated through G-protein coupled membrane receptors designated EP that includes EP1, EP2, EP3 and EP4. Our recent studies indicated that: (i) immortalized human endometriotic cells are ideal models to study molecular pathogenesis of endometriosis in women; and (ii) cyclooxygenase-2 (COX-2) promotes mitogenesis, migration and invasion of endometriotic cells in human. In this study, we used human endometriotic tissues and normal endometrium and the well characterized immortalized human endometriotic epithelial cells (12-Z) and stromal cells (22-B) as models to unravel PGE2 signaling in molecular pathogenesis of endometriosis in human. EP2 and EP4 receptors were abundantly expressed in endometriotic tissues compared to normal endometrium in women. Combined inhibition/silencing of EP2 and EP4 increased apoptosis of both epithelial and stromal cells by altering ratio between proapoptotic (Bax and Bad) and antiapoptotic (Bcl2 and Bcl-XL) proteins and through cytochrome-C, caspase 3 and poly ADP-ribose polymerase (PARP) pathways. Further, our data indicated that EP2 and EP4 signaling in endometriotic cell growth and survival is mediated through epidermal growth factor receptor (EGFR), Nuclear Factor kabba B (NFkB) and Wnt/b-catenine signaling pathways. Activation of these multiple intracellular signaling pathways in turn activated c-fos, c-jun and c-myc proteins. In conclusion, our data clearly indicate that PGE2 plays a central role in pathogenesis of endometriosis and targeting EP2 and EP4 signaling might be novel therapeutics for treatment of endometriosis in women. (platform)