Aromatase inhibition by 15-deoxy-prostaglandin J2 (15-dPGJ2) and N-(4-hydroxyphenyl)-retinamide (4HPR) is associated with enhanced ceramide production
Aromatase inhibition by 15-deoxy-prostaglandin J2 (15-dPGJ2) and N-(4-hydroxyphenyl)-retinamide (4HPR) is associated with enhanced ceramide production
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DOI：
10.1016/j.jsbmb.2005.01.014
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发表时间：
2005-02-01
影响因子：
4.1
通讯作者：
Schrey, MP
中科院分区：
文献类型：
--
作者：
Andrews, WJ;Winnett, G;Schrey, MP
抑制芳香化酶活性是一种成熟的内分泌疗法，用于治疗激素依赖性乳腺癌。最近关于合成类维甲酸4HPR（也称为芬维甲酸）和PPAR γ激动剂15-dPGJ(2)抑制芳香化酶的研究表明，其作用机制与受体直接无关，对氧化还原敏感。信号分子神经酰胺先前也被认为是芳香酶活性的负调节因子。在本研究中，我们研究了这种鞘脂在芬维甲酸和15-dPGJ2抑制乳腺癌细胞系MDA MB 231和JEG-3绒毛膜癌细胞中芳香化酶的潜在介导作用。4HPR和15-dPGJ2引起与神经酰胺产生增加相关的芳香酶活性的剂量依赖性抑制。这两种作用都是氧化还原敏感的，因为它们在抗氧化剂n -乙酰半胱氨酸的存在下被废除。外源性神经酰胺类似物模拟了这些对芳香化酶的抑制作用，但以氧化还原不依赖的方式。伏马菌素B或肉豆蔻素阻断新生神经酰胺产生途径可抑制神经酰胺反应，但不能阻止15-dPGJ2或4HPR对芳香化酶的抑制。本研究强调了15-dPGJ2和4HPR治疗乳腺癌过程中芳香化酶抑制和应激反应信号神经酰胺的潜在作用。然而，这些数据并不支持鞘脂在这些药物抑制芳香酶过程中的中介作用。(c) 2005 Elsevier Ltd版权所有。
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 PPAR gamma 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-dPGJ2 in the breast cancer cell line MDA MB 231 and JEG-3 choriocarcinoma cells.4HPR and 15-dPGJ2 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, or myriocin inhibited the ceramide responses, but did not prevent aromatase inhibition by 15-dPGJ2 or 4HPR.This study highlights a potential role for aromatase inhibition and the stress-response signal ceramide during the therapeutic actions of 15-dPGJ2 and 4HPR in breast cancer treatment. However, these data do not support a mediatory role for this sphingolipid during aromatase inhibition by these agents. (c) 2005 Elsevier Ltd. All rights reserved.