JeHoon Leea, Sakhila K. Banua, Thenmozhi Subbaraoa, Anna Starzinski-Powitzb, Joe A. Arosha
a Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, United States
b Molekulare Zellbiologie und Humangenetik, Institut fur Zellbiologie und Neurowissenschaft, Johann Wolfgang Goethe-Universitat, Siesmayerstraße 70, Geb. B, 60323 Frankfurt am Main, Germany
Corresponding author at: Department of Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Mail Stop: TAMU 4458, Texas A&M University, College Station, TX 77843, United States.
Abstract
Prostaglandin E2 (PGE2) plays an important role in the pathogenesis of endometriosis. We recently reported that inhibition of COX-2 decreased migration as well as invasion of human endometriotic epithelial and stromal cells. Results of the present study indicates that selective inhibition of PGE2 receptors EP2 and EP4 suppresses expression and/or activity of MMP1, MMP2, MMP3, MMP7 and MMP9 proteins and increases expression of TIMP1, TIMP2, TIMP3, and TIMP4 proteins and thereby decreases migration and invasion of human immortalized endometriotic epithelial and stromal cells into matrigel. The interactions between EP2/EP4 and MMPs are mediated through Src and β-arrestin 1 protein complex involving MT1-MMP and EMMPRIN in human endometriotic cells. These novel findings provide an important molecular and cellular framework for further evaluation of selective inhibition of EP2 and EP4 as potential nonsteroidal therapy for endometriosis in childbearing-age women.
Key words : PGE2; EP2 and EP4; Invasion; MMPs; Endometriosis; Human