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Selective Inhibition of Prostaglandin E2 Receptors EP2 and EP4 Induces Apoptosis of Human Endometriotic Cells through Suppression of ERK1/2, AKT, NFB, and β-Catenin Pathways and Activation of Intrinsic Apoptotic Mechanisms

Reproductive Endocrinology and Cell Signaling Laboratory (S.K.B., J.L., J.A.A.), Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843; Division of Anatomic Pathology (V.O.S.), Department of Pathology, Scott and White Memorial Hospital, Texas A&M University Health Science Center, Temple, Texas 76508; and Molekulare Zellbiologie und Humangenetik (A.S.-P.), Institut für Zellbiologie und Neurowissenschaft, Johann Wolfgang Goethe-Universität, 60323 Frankfurt am Main, Germany

Address all correspondence and requests for reprints to: Joe A. Arosh, Ph.D., Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Mail Stop TAMU 4458, Texas A&M University, College Station, Texas 77843. E-mail: jarosh{at}cvm.tamu.edu.

Endometriosis is a benign chronic gynecological disease of reproductive-age women characterized by the presence of functional endometrial tissues outside the uterine cavity. It is an estrogen-dependent disease. Current treatment modalities to inhibit biosynthesis and actions of estrogen compromise menstruation, pregnancy, and the reproductive health of women and fail to prevent reoccurrence of disease. There is a critical need to identify new specific signaling modules for non-estrogen-targeted therapies for endometriosis. In our previous study, we reported that selective inhibition of cyclooxygenase-2 prevented survival, migration, and invasion of human endometriotic epithelial and stromal cells, which was due to decreased prostaglandin E₂ (PGE₂) production. In this study, we determined mechanisms through which PGE₂ promoted survival of human endometriotic cells. Results of the present study indicate that 1) PGE₂ promotes survival of human endometriotic cells through EP2 and EP4 receptors by activating ERK1/2, AKT, nuclear factor-B, and β-catenin signaling pathways; 2) selective inhibition of EP2 and EP4 suppresses these cell survival pathways and augments interactions between proapoptotic proteins (Bax and Bad) and antiapoptotic proteins (Bcl-2/Bcl-XL), facilitates the release of cytochrome c, and thus activates caspase-3/poly (ADP-ribose) polymerase-mediated intrinsic apoptotic pathways; and 3) these PGE₂ signaling components are more abundantly expressed in ectopic endometriosis tissues compared with eutopic endometrial tissues during the menstrual cycle in women. These novel findings may provide an important molecular framework for further evaluation of selective inhibition of EP2 and EP4 as potential therapy, including nonestrogen target, to expand the spectrum of currently available treatment options for endometriosis in women.