Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer.
Autor: | Ho LL; Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia., Kench JG, Handelsman DJ, Scheffer GL, Stricker PD, Grygiel JG, Sutherland RL, Henshall SM, Allen JD, Horvath LG |
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Jazyk: | angličtina |
Zdroj: | The Prostate [Prostate] 2008 Sep 15; Vol. 68 (13), pp. 1421-9. |
DOI: | 10.1002/pros.20809 |
Abstrakt: | 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 DHT 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. ((c) 2008 Wiley-Liss, Inc.) |
Databáze: | MEDLINE |
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