title: Prostaglandin J2 metabolites inhibit aromatase activity by redox-sensitive mechanisms: potential implications for breast cancer therapy.
abstract: The mechanisms by which prostaglandin (PG)J(2) metabolites inhibit tumorigenicity are poorly understood but may involve thiol reactivity or peroxisome proliferator-activated receptor (PPAR)-dependent pathways. Because aromatase is an important therapeutic target in breast cancer treatment, we have investigated the effect of PGJ(2) metabolites on aromatase activity and evaluated a potential role for redox status during PGJ(2) metabolite action. 15-deoxy-Delta(12,14)PGJ(2) (15d-PGJ(2)) and 9-deoxy-Delta(9,12)13,14-dihydroPGD(2) (Delta(12)PGJ(2)) caused dose-dependent inhibition of both pre-induced aromatase activity in human breast fibroblasts and MDA MB 231 breast cancer cells and of constitutive aromatase activity in JEG-3 choriocarcinoma cells. Structure-activity studies showed that this inhibition was mimicked by 4-cyclopentene-1,3-dione but not by the PPARgamma agonist troglitazone nor the eicosanoids PGE(2) or arachidonic acid. The thiol oxidants diamide and H(2)O(2) simulated the inhibitory action of 15d-PGJ(2) on aromatase activity, whereas the glutathione (GSH) repletor and antioxidant N-acetyl-cysteine (NAC) reversed these actions of 15d-PGJ(2) and H(2)O(2) on aromatase. 15d-PGJ(2) also caused a direct dose-dependent inhibition of aromatase activity in JEG-3 cell sonicates, which was also reversed in the presence of GSH. Kinetic analysis of this 15d-PGJ(2)-induced inhibition of cell-free aromatase indicated the involvement of a non-competitive mechanism possibly resulting from direct thiol-targeted alkylation of the enzyme. These redox-sensitive, PPARgamma-independent actions of 15d-PGJ(2) on aromatase activity demonstrate a novel therapeutic potential for such cyclopentenone PGs in breast cancer treatment.
authors.affiliation: Endocrinology and Metabolic Medicine, Division of Medicine, Faculty of Medicine, Imperial College of Science Technology and Medicine, London, United Kingdom.
authors.forename: Georgia
authors.initials: G
authors.lastname: Winnett
authors.forename: Daphne
authors.initials: D
authors.lastname: van Hagen
authors.forename: Michael
authors.initials: M
authors.lastname: Schrey
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D010084:Oxidation-Reduction; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000975:Antioxidants; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D013439:Sulfhydryl Reagents; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D001141:Aromatase; D005978:Glutathione; D015230:Prostaglandin D2; D000111:Acetylcysteine