title: Opposing Effects of Cyclooxygenase-2 (COX-2) on Estrogen Receptor β (ERβ) Response to 5α-Reductase Inhibition in Prostate Epithelial Cells.
abstract: Current pharmacotherapies for symptomatic benign prostatic hyperplasia (BPH), an androgen receptor-driven, inflammatory disorder affecting elderly men, include 5α-reductase (5AR) inhibitors (i.e. dutasteride and finasteride) to block the conversion of testosterone to the more potent androgen receptor ligand dihydrotestosterone. Because dihydrotestosterone is the precursor for estrogen receptor β (ERβ) ligands, 5AR inhibitors could potentially limit ERβ activation, which maintains prostate tissue homeostasis. We have uncovered signaling pathways in BPH-derived prostate epithelial cells (BPH-1) that are impacted by 5AR inhibition. The induction of apoptosis and repression of the cell adhesion protein E-cadherin by the 5AR inhibitor dutasteride requires both ERβ and TGFβ. Dutasteride also induces cyclooxygenase type 2 (COX-2), which functions in a negative feedback loop in TGFβ and ERβ signaling pathways as evidenced by the potentiation of apoptosis induced by dutasteride or finasteride upon pharmacological inhibition or shRNA-mediated ablation of COX-2. Concurrently, COX-2 positively impacts ERβ action through its effect on the expression of a number of steroidogenic enzymes in the ERβ ligand metabolic pathway. Therefore, effective combination pharmacotherapies, which have included non-steroidal anti-inflammatory drugs, must take into account biochemical pathways affected by 5AR inhibition and opposing effects of COX-2 on the tissue-protective action of ERβ.
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Liu
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Grubisha
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Krystle A
authors.initials: KA
authors.lastname: Frahm
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Stacy G
authors.initials: SG
authors.lastname: Wendell
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Departments of Internal Medicine and Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, and.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Urology, University of Wisconsin, Madison, Wisconsin 53705.
authors.forename: William A
authors.initials: WA
authors.lastname: Ricke
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Departments of Internal Medicine and Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, dod1@pitt.edu.
authors.forename: Donald B
authors.initials: DB
authors.lastname: DeFranco
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D000068538:Dutasteride / Q000494:pharmacology*; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000502:physiology*; D006801:Humans; D008297:Male; D011453:Prostaglandins / Q000096:biosynthesis; D011467:Prostate / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*
chemical_list: D058891:5-alpha Reductase Inhibitors; D047629:Estrogen Receptor beta; D011453:Prostaglandins; D051546:Cyclooxygenase 2; D000068538:Dutasteride
keywords: cyclooxygenase (COX); prostaglandin; prostate; steroidogenesis; transforming growth factor β (TGF-β)