ah-23848 and Endometriosis

Endometriosis is an inflammatory gynecological disease of reproductive-age women. The prevalence of endometriosis is 5-10% in reproductive-age women. Modern medical treatments are directed to inhibit the action of estrogen in endometriotic cells. However, hormonal therapies targeting estrogen can be prescribed only for a short time because of their undesirable side effects. Recent studies from our laboratory, using human endometriotic epithelial cell line 12Z and stromal cell line 22B derived from red lesion, discovered that selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits adhesion, invasion, growth, and survival of 12Z and 22B cells by modulating integrins, MMPs and TIMPs, cell cycle, survival, and intrinsic apoptotic pathways, suggesting multiple epigenetic mechanisms. The novel findings of the present study indicate that selective pharmacological inhibition of EP2 and EP4: (i) decreases expression of DNMT3a, DNMT3b, H3K9me3, H3K27me3, SUV39H1, HP1a, H3K27, EZH2, JMJD2a, HDAC1, HDAC3, MeCP2, CoREST and Sin3A; (ii) increases expression of H3K4me3, H3H9ac, H3K27ac; and (iii) does not modulate the expression of DNMT1, hSET1, LSD1, MBD1, p300, HDAC2, and JMJD3 epigenetic machinery proteins in an epithelial and stromal cell specific manner. In this study, we report for the first time that inhibition of PGE2-EP2/EP4 signaling modulates DNA methylation, H3 histone methylation and acetylation, and epigenetic memory machinery proteins in human endometriotic epithelial cells and stromal cells. Thus, targeting EP2 and EP4 receptors may emerge as long-term nonsteroidal therapy for treatment of active endometriotic lesions in women.

Topics: Acetylation; Biphenyl Compounds; Cell Line; DNA Methylation; Endometriosis; Epigenesis, Genetic; Female; Gene Expression Regulation; Histones; Humans; Prostaglandin Antagonists; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Xanthones

Endometriosis is a debilitating, estrogen-dependent, progesterone-resistant, inflammatory gynecological disease of reproductive age women. Two major clinical symptoms of endometriosis are chronic intolerable pelvic pain and subfertility or infertility, which profoundly affect the quality of life in women. Current hormonal therapies to induce a hypoestrogenic state are unsuccessful because of undesirable side effects, reproductive health concerns, and failure to prevent recurrence of disease. There is a fundamental need to identify nonestrogen or nonsteroidal targets for the treatment of endometriosis. Peritoneal fluid concentrations of prostaglandin E2 (PGE2) are higher in women with endometriosis, and this increased PGE2 plays important role in survival and growth of endometriosis lesions. The objective of the present study was to determine the effects of pharmacological inhibition of PGE2 receptors, EP2 and EP4, on molecular and cellular aspects of the pathogenesis of endometriosis and associated clinical symptoms. Using human fluorescent endometriotic cell lines and chimeric mouse model as preclinical testing platform, our results, to our knowledge for the first time, indicate that selective inhibition of EP2/EP4: (i) decreases growth and survival of endometriosis lesions; (ii) decreases angiogenesis and innervation of endometriosis lesions; (iii) suppresses proinflammatory state of dorsal root ganglia neurons to decrease pelvic pain; (iv) decreases proinflammatory, estrogen-dominant, and progesterone-resistant molecular environment of the endometrium and endometriosis lesions; and (v) restores endometrial functional receptivity through multiple mechanisms. Our novel findings provide a molecular and preclinical basis to formulate long-term nonestrogen or nonsteroidal therapy for endometriosis.

Topics: Animals; Apoptosis; Biphenyl Compounds; Caspase 3; Cell Line; Cell Movement; Cell Survival; Disease Models, Animal; Endometriosis; Endometrium; Estrogens; Female; Humans; Inflammation; Mice; Neovascularization, Pathologic; Pelvic Pain; Poly(ADP-ribose) Polymerases; Progesterone; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Steroids; Xanthones

To determine interactions between prostaglandin (PG) E(2) signaling and proliferation of endometriotic cells to increase our knowledge about PGE(2) signaling in the pathogenesis of endometriosis in humans.. Immortalized human endometriotic epithelial and stromal cells were used as an in vitro model. Effects of inhibition of PGE(2) receptors on proliferation of endometriotic cells and associated cell cycle regulation were determined.. College Veterinary Medicine and Biomedical Sciences, Texas A&M University.. Not available.. None.. Cell proliferation, cell viability, cell cycle, regulation of cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors.. Selective blockade of EP2/EP4 inhibited proliferation of human endometriotic cells by inducing cell cycle arrest at the G(1)-S and G(2)-M checkpoints in epithelial cells and at the G(2)-M checkpoint in stromal cells. This cell cycle arrest during specific checkpoints was associated with distinct regulation of respective cyclins and cyclin-dependent kinases. Inhibition of EP1 did not decrease endometriotic cell proliferation.. For the first time data from the present study provide a direct molecular link between PGE(2) signaling and proliferation of endometriotic cells and suggest that inhibition of EP2/EP4 could be a potential nonestrogen (E) treatment option for endometriosis in women.

Topics: Biphenyl Compounds; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinases; Endometriosis; Endometrium; Female; Humans; Prostaglandin Antagonists; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; RNA, Small Interfering; Signal Transduction; Stromal Cells; Xanthones