Stabilization of androgen receptor protein is induced by agonist, not by antagonists.
The action of nuclear receptor ligands in target tissues is specified mainly by the expression levels of their cognate nuclear receptors. The expression levels of these receptors are controlled through transcriptional and post-transcriptional events. Among post-transcriptional events, the effect of ligand on nuclear receptor protein turnover still remains largely unknown. Therefore, we studied the effects of agonist and antagonists on the turnover of the human androgen receptor (hAR) protein in stably transformed Chinese hamster ovary cells expressing exogenous hAR. Western blot analysis showed that the most potent androgen, dihydrotestosterone (DHT), stabilizes hAR with the induction of the transactivation function of hAR. However, this androgen-induced stabilization of hAR protein was abrogated by well-known androgen antagonists, hydroxyflutamide and bicalutamide (BIC), with inhibition of the transactivation function of hAR. Thus, the present study suggests that androgen antagonists exert their effects through, at least in part, abrogating the agonist-induced stabilization of hAR protein as well as blocking the ligand-induced transactivation function of hAR.
Furutani
Takashi
T
Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba 305-8585, Japan.
Watanabe
Tomoyuki
T
Tanimoto
Kyouko
K
Hashimoto
Takamichi
T
Koutoku
Hiroshi
H
Kudoh
Masafumi
M
Shimizu
Yasuaki
Y
Kato
Shigeaki
S
Shikama
Hisataka
H
D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D009570:Nitriles; D010957:Plasmids; D012323:RNA Processing, Post-Transcriptional; D011944:Receptors, Androgen / Q000378:metabolism*; D013997:Time Factors; D014105:Tosyl Compounds; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D008024:Ligands; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D005485:Flutamide; C053541:bicalutamide; D008156:Luciferases