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 PPARγ 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.