title: Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis.
abstract: 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.
authors.affiliation: Department of Integrative Biosciences, Texas A&M University, College Station, TX 77843; jarosh@cvm.tamu.edu skbanu@cvm.tamu.edu.
authors.forename: Joe A
authors.initials: JA
authors.lastname: Arosh
authors.affiliation: Department of Integrative Biosciences, Texas A&M University, College Station, TX 77843;
authors.forename: JeHoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Integrative Biosciences, Texas A&M University, College Station, TX 77843;
authors.forename: Dakshnapriya
authors.initials: D
authors.lastname: Balasubbramanian
authors.affiliation: Department of Integrative Biosciences, Texas A&M University, College Station, TX 77843;
authors.forename: Jone A
authors.initials: JA
authors.lastname: Stanley
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843;
authors.forename: Charles R
authors.initials: CR
authors.lastname: Long
authors.affiliation: Department of Psychology, College of Liberal Arts, Texas A&M University, College Station, TX 77843;
authors.forename: Mary W
authors.initials: MW
authors.lastname: Meagher
authors.affiliation: Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Osteen
authors.affiliation: Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Kaylon L
authors.initials: KL
authors.lastname: Bruner-Tran
authors.affiliation: Department of Integrative Biosciences, Texas A&M University, College Station, TX 77843;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Burghardt
authors.affiliation: Biosciences, Molecular Cell Biology and Human Genetics, Goethe University, Frankfurt am Main 60483, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Starzinski-Powitz
authors.affiliation: Department of Integrative Biosciences, Texas A&M University, College Station, TX 77843; jarosh@cvm.tamu.edu skbanu@cvm.tamu.edu.
authors.forename: Sakhila K
authors.initials: SK
authors.lastname: Banu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy* / Q000473:pathology*; D004717:Endometrium / Q000098:blood supply / Q000473:pathology; D004967:Estrogens / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D017699:Pelvic Pain / Q000188:drug therapy / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000627:therapeutic use; D044004:Xanthones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001713:Biphenyl Compounds; D004967:Estrogens; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013256:Steroids; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D011374:Progesterone; C046926:AH 23848; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3
keywords: PGE2 signaling; endometriosis; infertility; pain pathways; pelvic pain