JeHoon Lee3, Sakhila K. Banu3, Robert C. Burghardt4, Anna Starzinski-Powitz5, and Joe A. Arosh2,3
3Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
4Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
5Molekulare Zellbiologie und Humangenetik, Institut fur Zellbiologie und Neurowissenschaft, Frankfurt am Main, Germany
2 Correspondence: Joe A. Arosh, Department of Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Mail Stop: TAMU 4458, Texas A&M University, College Station, Texas 77843.
ABSTRACT
Endometriosis is a chronic gynecological disease of reproductive age women characterized by the presence of functional endometrial tissues outside the uterine cavity. Interactions between the endometriotic cells and the peritoneal extracellular matrix proteins (ECM) are crucial mechanisms that allow adhesion of the endometriotic cells into peritoneal mesothelia. Prostaglandin E2 (PGE2) plays an important role in the pathogenesis of endometriosis. In previous studies, we have reported that selective inhibition of PGE2 receptors PTGER2 and PTGER4 decreases survival and invasion of human endometriotic epithelial and stromal cells through multiple mechanisms. Results of the present study indicates that selective inhibition of PTGER2- and PTGER4-mediated PGE2 signaling 1) decreases the expression and/or activity of specific integrin receptor subunits Itgb1 (beta1) and Itgb3 (beta3) but not Itgb5 (beta5), Itga1 (alpha1), Itga2 (alpha2), Itga5 (alpha5), and Itgav (alphav); 2) decreases integrin-signaling components focal adhesion kinase or protein kinase 2 (PTK2) and talin proteins; 3) inhibits interactions between Itgb1/Itgb3 subunits, PTK2, and talin and PTGER2/PTGER4 proteins through beta-arrestin-1 and Src kinase protein complex in human endometriotic epithelial cells 12Z and stromal cells 22B; and 4) decreases adhesion of 12Z and 22B cells to ECM collagen I, collagen IV, fibronectin, and vitronectin in a substrate-specific manner. These novel findings provide an important molecular framework for further evaluation of selective inhibition of PTGER2 and PTGER4 as potential nonsteroidal therapy to expand the spectrum of currently available treatment options for endometriosis in child-bearing age women.
adhesion, endometriosis, human, integrins, PGE2
1 Supported in part by National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) and Office of Research on Women's Health (1R21HD065138-01A1 and 1R21HD066248-01A1 to J.A.A.).