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Prostaglandin J 2 metabolites inhibit aromatase activity by redox‐sensitive mechanisms: Potential implications for breast cancer therapy
Author(s) -
Winnett Georgia,
van Hagen Daphne,
Schrey Michael
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10878
Subject(s) - aromatase , glutathione , chemistry , prostaglandin , medicine , endocrinology , prostaglandin d2 , pharmacology , biochemistry , biology , enzyme , breast cancer , cancer
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‐Δ 12,14 PGJ 2 (15d‐PGJ 2 ) and 9‐deoxy‐Δ 9,12 13,14‐dihydroPGD 2 (Δ 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 PPARγ 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, PPARγ‐independent actions of 15d‐PGJ 2 on aromatase activity demonstrate a novel therapeutic potential for such cyclopentenone PGs in breast cancer treatment. © 2002 Wiley‐Liss, Inc.