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


CONCLUSIONS
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.
Ho
Lye Lin
LL
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW 2042, Australia.
Kench
James G
JG
Handelsman
David J
DJ
Scheffer
George L
GL
Stricker
Phillip D
PD
Grygiel
John G
JG
Sutherland
Robert L
RL
Henshall
Susan M
SM
Allen
John D
JD
Horvath
Lisa G
LG
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000502:physiology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000726:Androgen Antagonists; D000728:Androgens; D013196:Dihydrotestosterone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D013739:Testosterone; C073492:ABCC4 protein, human