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 associa ted with a marked increase in dehydroepiandrosterene/hydroxysteroid su lfotransferase (rStd) activity. Sulfonated steroid hormones are known to be ineffective in binding receptor proteins. These observations sug gest that intracellular androgen sulfonation can physiologically influ ence androgen action. We have examined the inhibitory effect of rStd o n androgen action in the human prostate cancer-derived PC-3 cells tran sfected with the rat androgen receptor (AR) expression plasmid and two androgen-responsive promoter-reporter constructs (murine mammary tumo r long-terminal repeat ligated to chloramphenicol acetyltransferase (C AT) gene and rat probasin androgen response element (ARE) ligated to f irefly luciferase (LUC) gene). These transfected cells were dependent on Sa-dihydrotestosterone (DHT for the activation of both reporter gen es and showed about a 200- and a 800-fold increase of CAT and LUC acti vity, respectively, at 10(-10) M DHT over the no-hormone control. Expr ession of the sulfonating enzyme in this cell transfection system via the rStd expression plasmid caused a dose-dependent decline in the rep orter activity with approximate to 90% inhibition of androgen action a t 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. (C) 1998 Else vier Science Ireland Ltd. All rights reserved.