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

Sakhila K. Banu, JeHoon Lee, V. O. Speights, Anna Starzinski‐Powitz, Joe A. Arosh
In: The Journal of Clinical Endocrinology & Metabolism · 2009 · vol. 94(7) , pp. 2673 · doi:10.1210/jcem.94.7.9993 · W3212370733
article OA: bronze CC0 ⤵ 15 in-corpus citations
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Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis in human endometriotic cells by suppressing key survival pathways and activating intrinsic apoptotic mechanisms.

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Abstract

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, 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 PGE2 production. In this study, we determined mechanisms through which prostaglandin E2 (PGE2) promoted survival of human endometriotic cells. Results of the present study indicate that: (i) PGE2 promotes survival of human endometriotic cells through EP2 and EP4 receptors by activating ERK1/2, AKT, NFκB, and β-catenin signaling pathways; (ii) 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/PARP-mediated intrinsic apoptotic pathways; and (iii) these PGE2 signaling components are more abundantly expressed in ectopic endometriosis tissues compared to 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 non-estrogen target, to expand the spectrum of currently available treatment options for endometriosis in women.

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endometriosis

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