Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits adhesion, migration, and invasion of human endometriotic cells

Abstract

OBJECTIVE: Prostaglandin E2 plays an important role in the pathogenesis of endometriosis. The objective of the present study was to determine functional interaction between PGE2 signaling and adhesion, migration, and invasion of human endometriotic epithelial and stromal cells and to unravel the underlying molecular and cellular mechanisms. DESIGN: Human immortalized endometriotic epithelial and stromal cells were treated with EP2 and EP4 receptor inhibitors, and their effects on adhesion, migration, and invasion of cells were studied and the underlined molecular mechanisms were uncovered. MATERIALS AND METHODS: Adhesion of endometriotic cells with ECM substrate and invasion of endometriotic ells into matrigel were analyzed in vitro. Set of integrins, MMPs and TIMPS proteins were analyzed by western blot. RESULTS: Results of the present study indicated that selective inhibition of EP2 and EP4-mediated PGE2 signaling: (i) suppressed expression and/or activity specific integrin receptors a2b1, avb3, a5b1, and a3b1 and thereby decreased adhesion of human endometriotic epithelial and stromal cells to extracellular matrix substrates collagen I, collagen IV, vitronectin, fibronectin, and laminins; and (ii) suppressed expression and/or activity of MMP1, MPP2, MMP3, MMP7 and MMP9 and increased expression of TIMP1, TIMP2, TIMP3, and TIMP4 and thereby decreased migration and invasion of human endometriotic epithelial and stromal cells. CONCLUSION: These novel findings may provide an important molecular framework for further evaluation of selective inhibition of EP2 and EP4 as potential nonestrogen or nonsteroidal therapy to expand the spectrum of currently available treatment options for endometriosis in child-bearing age women. Further, our results suggest potential opportunities for translational studies that could lead to preclinical and clinical-phase trials.