P-glycoprotein increases the efflux of the androgen dihydrotestosterone and reduces androgen responsive gene activity in prostate tumor cells
P-glycoprotein increases the efflux of the androgen dihydrotestosterone and reduces androgen responsive gene activity in prostate tumor cells
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DOI：
10.1002/pros.10354
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发表时间：
2004-04-01
期刊：
影响因子：
2.8
通讯作者：
Nelson, CC
中科院分区：
文献类型：
--
作者：
Fedoruk, MN;Giménez-Bonafé, P;Nelson, CC
背景P-糖蛋白（P-gp）通常与癌细胞中的多药耐药性（MDR）和广谱化学物质（包括许多化疗药物和某些类固醇激素）从细胞中流出有关。P-gp对正常和恶性前列腺细胞内雄激素转运和细胞积聚的影响及其机制尚不清楚。在LNCaP、PC-3、HeLa和HeLa FLAG雄激素受体（AR）细胞与H-3-双氢睾酮（DHT）单独孵育以及与P-gp抑制剂PSC-833和维拉帕米联合孵育后，我们检测了雄激素的细胞蓄积和流出以及基因转录反应。我们的数据表明，细胞转运和积累的DHT是依赖于功能性AR的表达和P-gp的调制。瞬时转染和阿司匹林处理后LNCaP细胞中P-gp过表达均显示细胞内DHT蓄积减少，进一步表明DHT外排受P-gp调节。P-gp可调节前列腺癌细胞的雄激素反应性。P-gp表达增加的生物学后果是雄激素积累减少，雄激素调节的转录活性和PSA基因表达相应降低。(C)2003 Wiley-Liss，Inc.
BACKGROUND. P-glycoprotein (P-gp) is commonly associated with multi-drug resistance (MDR) in cancer cells and the efflux of a broad spectrum of chemicals from the cell, including many chemotherapeutics and certain steroid hormones. The impact of P-gp and mechanisms involved in androgen transport and cellular accumulation within normal and malignant prostate cells remains unclear.METHODS. Following incubation of LNCaP, PC-3, HeLa, and HeLa FLAG-androgen receptor (AR) cells with H-3-dihydrotestosterone (DHT) alone and in combination with P-gp inhibitors, PSC-833 and verapamil, we examined the cellular accumulation and efflux of androgens, as well as gene transcriptional response.RESULTS. Our data reveal that the cellular transport and accumulation of DHT is dependent on the expression of functional AR and modulated by P-gp. P-gp over-expression by both transient transfection and aspirin treatment in LNCaP cells showed decreased intracellular DHT accumulation, further suggesting DHT efflux is P-gp regulated.CONCLUSIONS. Androgen responsiveness may be modulated by P-gp in prostate cancer cells. The biological consequences of increased P-gp expression are decreased androgen accumulation and a corresponding decrease in androgen-regulated transcriptional activity and PSA gene expression. (C) 2003 Wiley-Liss, Inc.