1alpha,25-Dihydroxyvitamin D3 down-regulates expression of prostate specific membrane antigen in prostate cancer cells.
BACKGROUND
Prostate specific membrane antigen (PSMA) expression correlates with prostate cancer grade and is increased in hormone-refractory prostate cancer. The increased expression of PSMA following androgen deprivation therapy may be a consequence of the down-regulation of PSMA expression by androgen. Moreover, 1alpha,25-dihydroxyvitamin D3 (1,25-VD) has been shown to suppress prostate cancer progression as well as cell motility and invasion. Since PSMA is positively correlated with both of these characteristics, we hypothesized that 1,25-VD would regulate PSMA expression.


METHODS
LNCaP prostate cancer cells were treated with 1,25-VD, followed by analysis of cell surface PSMA expression. The PSMA enhancer, located within the third intron of the PSMA gene, was cloned into a reporter vector and regulation by 1,25-VD was investigated. The role of the androgen receptor (AR) in 1,25-VD mediated suppression of PSMA expression was examined using Casodex and AR specific siRNA.


RESULTS
Surface expression of PSMA was significantly decreased in a dose-dependent manner by 10 nM 1,25-VD or greater. Regulation by 1,25-VD occurred at the level of the PSMA enhancer. Over-expression of the vitamin D receptor (VDR) also decreased expression of PSMA. Additionally, suppression of AR translation using siRNA technology blocked the suppressive effect of 1,25-VD on PSMA expression, however inhibition of PSMA expression by 1,25-VD occurred in the absence of androgens.


CONCLUSIONS
Suppression of PSMA by 1,25-VD occurs at the level of the PSMA enhancer and is elevated by over-expression of the VDR. This regulation involves the AR, but is not dependent on the presence of androgens.
Serda
Rita E
RE
Brown Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA. rita.serda@uth.tmc.edu
Bisoffi
Marco
M
Thompson
Todd A
TA
Ji
Ming
M
Omdahl
John L
JL
Sillerud
Laurel O
LO
D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D002117:Calcitriol