Inhibition of androgen action by dehydroepiandrosterone sulfotransferase transfected in PC-3 prostate cancer cells.
Age-dependent loss of androgen sensitivity of the rat liver is associated with a marked increase in dehydroepiandrosterone/hydroxysteroid sulfotransferase (rStd) activity. Sulfonated steroid hormones are known to be ineffective in binding receptor proteins. These observations suggest that intracellular androgen sulfonation can physiologically influence androgen action. We have examined the inhibitory effect of rStd on androgen action in the human prostate cancer-derived PC-3 cells transfected with the rat androgen receptor (AR) expression plasmid and two androgen-responsive promoter reporter constructs (murine mammary tumor long-terminal repeat ligated to chloramphenicol acetyltransferase (CAT) gene and rat probasin androgen response element (ARE) ligated to firefly luciferase (LUC) gene). These transfected cells were dependent on 5alpha-dihydrotestosterone (DHT) for the activation of both reporter genes and showed about a 200- and a 800-fold increase of CAT and LUC activity, respectively, at 10(-10) M DHT over the no-hormone control. Expression of the sulfonating enzyme in this cell transfection system via the rStd expression plasmid caused a dose-dependent decline in the reporter activity with approximately 90% inhibition of androgen action at a rStd:AR plasmid ratio of 100. From these results we conclude that irrespective of a high level of AR, changes in the Std expression can markedly alter the androgen sensitivity of target cells.
Chan
J
J
Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 78284-7762, USA.
Song
C S
CS
Matusik
R J
RJ
Chatterjee
B
B
Roy
A K
AK
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics*; D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000728:Androgens / Q000502:physiology*; D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000201:enzymology / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D051381:Rats; D012091:Repetitive Sequences, Nucleic Acid; D015238:Sulfotransferases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D000728:Androgens; D013196:Dihydrotestosterone; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D015238:Sulfotransferases; C019998:dehydroepiandrosterone sulfotransferase