Prostaglandin J2 metabolites inhibit aromatase activity by redox‐sensitive mechanisms: Potential implications for breast cancer therapy

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Abstract
The mechanisms by which prostaglandin (PG)J2 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 PGJ2 metabolites on aromatase activity and evaluated a potential role for redox status during PGJ2 metabolite action. 15-deoxy-Δ12,14PGJ2 (15d-PGJ2) and 9-deoxy-Δ9,1213,14-dihydroPGD2 (Δ12PGJ2) 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 PPARγ agonist troglitazone nor the eicosanoids PGE2 or arachidonic acid. The thiol oxidants diamide and H2O2 simulated the inhibitory action of 15d-PGJ2 on aromatase activity, whereas the glutathione (GSH) repletor and antioxidant N-acetyl-cysteine (NAC) reversed these actions of 15d-PGJ2 and H2O2 on aromatase. 15d-PGJ2 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-PGJ2-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, PPARγ-independent actions of 15d-PGJ2 on aromatase activity demonstrate a novel therapeutic potential for such cyclopentenone PGs in breast cancer treatment.