title: Aromatase inhibition by 15-deoxy-prostaglandin J(2) (15-dPGJ(2)) and N-(4-hydroxyphenyl)-retinamide (4HPR) is associated with enhanced ceramide production.
abstract: Inhibition of aromatase activity is an established endocrine therapy in the treatment of hormone-dependent breast cancer. Recent studies on aromatase inhibition by the synthetic retinoid 4HPR, also known as fenretinide, and the PPARgamma agonist 15-dPGJ(2) have implicated a direct receptor-independent, redox-sensitive mechanism of action. The signalling molecule ceramide has also been previously implicated as a negative regulator of aromatase activity. In the present study, we have investigated a potential mediatory role for this sphingolipid during aromatase inhibition by fenretinide and 15-dPGJ(2) in the breast cancer cell line MDA MB 231 and JEG-3 choriocarcinoma cells. 4HPR and 15-dPGJ(2) caused a dose-dependent inhibition of aromatase activity associated with an increase in ceramide production. Both these actions were redox-sensitive as demonstrated by their abrogation in the presence of the anti-oxidant N-acetylcysteine. Exogenous ceramide analogue mimicked these inhibitory actions on aromatase, but in a redox-independent manner. Blockade of the de novo ceramide production pathway by fumonisin B(1) or myriocin inhibited the ceramide responses, but did not prevent aromatase inhibition by 15-dPGJ(2) or 4HPR. This study highlights a potential role for aromatase inhibition and the stress-response signal ceramide during the therapeutic actions of 15-dPGJ(2) and 4HPR in breast cancer treatment. However, these data do not support a mediatory role for this sphingolipid during aromatase inhibition by these agents.
authors.affiliation: Section of Endocrinology and Metabolic Medicine, Imperial College London, St Mary's Hospital, Praed Street, London W2 1NY, UK.
authors.forename: William J
authors.initials: WJ
authors.lastname: Andrews
authors.forename: Georgia
authors.initials: G
authors.lastname: Winnett
authors.forename: Farah
authors.initials: F
authors.lastname: Rehman
authors.forename: Pradeep
authors.initials: P
authors.lastname: Shanmugasundaram
authors.forename: Daphne van
authors.initials: Dv
authors.lastname: Hagen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schrey
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013107:Sphingolipids / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D047072:Aromatase Inhibitors; D002518:Ceramides; D013107:Sphingolipids; D017313:Fenretinide; D001141:Aromatase; D015230:Prostaglandin D2