Received for publication July 23, 2004.
Revised November 22, 2004.
Accepted for publication November 22, 2004.

The Non-genotropic Synthetic Ligand Estren (4-estren- 317-diol) is a High Affinity Genotropic Androgen Receptor Agonist

Abstract

The non-genotropic ligand estren was evaluated for its transcriptional activity mediated by the human androgen receptor (AR). Our results show that estren can bind, translocate, transactivate, and regulate 2 known target genes of AR in androgen responsive cell lines. Estren binds recombinant AR with 10 fold higher affinity than either ER or ER. Estren bound AR can translocate AR to the nucleus and stimulate the ARE-luciferase reporter activity with an efficacy similar to androgen. Estren also increased the expression of PSA in a dose-dependent manner in human LnCAP cells. Using ChIP analysis we show that the estren-bound AR co-immunoprecipitates with a region of the PSA promoter. Accordingly, co-treatment with an AR antagonist, bicalutamide, blocked the estren- induced increase in PSA expression. In contrast, PI3K inhibitor Wortmannin, or ERK inhibitor U0126, and ER antagonist ICI-182780 failed to block the effects of estren. In vivo analysis of estren's action on male orchidectomized ICR mice, revealed estren's AR agonist actions on the levator ani and seminal vesicle target tissues. Collectively, our results reveal the hitherto unidentified genotropic action of estren mediated by AR in androgen responsive cells and tissues.

Key words: Sex hormones, Regulation of gene expression

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