Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer
Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer
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DOI：
10.1002/pros.20809
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发表时间：
2008-09-15
期刊：
影响因子：
2.8
通讯作者：
Horvath, Lisa G.
中科院分区：
文献类型：
--
作者：
Ho, Lye Lin;Kench, James G.;Horvath, Lisa G.
背景MRP 4/ABCC 4是一种在正常前列腺中表达的ATP结合盒转运蛋白。本研究旨在明确MRP 4/ABCC 4在正常和恶性前列腺组织中的表达模式，以及MRP 4/ABCC 4表达与雄激素信号应答功能的关系。对84例局限性前列腺癌（PC）患者（22例新辅助雄激素消融，AA，62例无AA）、42例非癌和16例晚期PC的根治性前列腺切除术标本进行了MRP 4/ABCC 4 mRNA/蛋白表达评估。通过免疫印迹法评估IDHT和比卡鲁胺对LNCaP细胞的作用。评估HEK 293细胞（+/-MRP 4/ABCC 4）流出雄激素和抗雄激素的能力。MRP 4/ABCC 4 mRNA/蛋白水平在局限性PC中高于非癌（P = 0.006）。与暴露于正常睾酮水平的癌症相比，AA治疗的PC中的MRP 4/ABCC 4水平显著降低（P < 0.0001）。MRP 4/ABCC 4在正常人体组织中的表达仅限于前列腺和肾小管。DHT后LNCaP细胞中MRP 4/ABCC 4蛋白水平增加，这被比卡鲁胺部分阻断。然而，在荧光素酶报告基因测定中，DHT并不改变MRP 4/ABCC 4启动子的激活，睾酮、DHT、氟替卡松和羟基氟替卡松不是MRP 4/ABCC 4的底物。与良性前列腺组织相比，恶性前列腺组织中的MRP 4/ABCC 4表达升高，而AA后的MRP 4/ABCC 4表达较低。此外，MRP 4/ABCC 4在体外可能通过间接作用模式被雄激素上调并被抗雄激素治疗下调。这些数据有力地表明，MRP 4/ABCC 4是一个雄激素调节基因，在PC的进展中很重要，可能是一个潜在的药物靶点。
BACKGROUND. MRP4/ABCC4 is an ATP-binding cassette transporter expressed in normal prostate. This study aimed to define the pattern of MRP4/ABCC4 expression in normal and malignant prostate tissue and the relationship of MRP4/ABCC4 expression and function in response to androgen signaling.METHODS. Eighty-four radical prostatectomy specimens from patients with localized prostate cancer (PC) (22 neoadjuvant androgen ablation, AA, 62 no AA), 42 non-cancer and 16 advanced PCs were assessed for MRP4/ABCC4 mRNA/protein expression. The effect of IDHT and bicalutamide on LNCaP cells was assessed by immunoblotting. HEK293 cells (+/-MRP4/ABCC4) were assessed for the ability to efflux androgens and anti-androgens.RESULTS. MRP4/ABCC4 mRNA/protein levels were higher in localized PC compared to non-cancer (P = 0.006). MRP4/ABCC4 levels were significantly decreased in PCs treated with AA compared to cancers exposed to normal testosterone levels (P < 0.0001). MRP4/ABCC4 expression in normal human tissues was limited to the prostate and the renal tubules. MRP4/ABCC4 protein levels increased in LNCaP cells after DHT which was partially blocked by bicalutamide. However, DHT did not alter the activation of the MRP4/ABCC4 promotor in luciferase reporter assays and testosterone, DHT, flutamide and hydroxy-flutamide were not substrates for MRP4/ABCC4.DISCUSSION. Elevated MRP4/ABCC4 expression is found in malignant compared to benign prostate tissue while lower MRP4/ABCC4 expression is seen after AA. Furthermore, MRP4/ABCC4 is upregulated by androgen and downregulated by anti-androgen treatment in vitro potentially through an indirect mode of action. These data strongly suggest that MRP4/ABCC4 is an androgen-regulated gene important in the progression to PC and may be a potential drug target.