Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer.

Abstract

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.

• Authors: Lye Lin Ho, James G Kench, David J Handelsman, George L Scheffer, Phillip D Stricker, John G Grygiel, Robert L Sutherland, Susan M Henshall, John D Allen, Lisa G Horvath
• Journal: The Prostate (Prostate) Vol. 68 Issue 13 Pg. 1421-9 (Sep 15 2008) ISSN: 1097-0045 [Electronic] United States
• PMID: 18615486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• ABCC4 protein, human
• Androgen Antagonists
• Androgens
• Multidrug Resistance-Associated Proteins
• RNA, Messenger
• Dihydrotestosterone
• Testosterone

Topics

• Adenocarcinoma (metabolism, pathology)
• Aged
• Androgen Antagonists (pharmacology)
• Androgens (physiology)
• Case-Control Studies
• Cell Line, Tumor
• Cohort Studies
• Dihydrotestosterone (pharmacology)
• Down-Regulation (drug effects)
• Humans
• Male
• Middle Aged
• Multidrug Resistance-Associated Proteins (metabolism)
• Prostatic Neoplasms (metabolism, pathology)
• RNA, Messenger (metabolism)
• Testosterone (pharmacology)
• Up-Regulation (drug effects)