Non-steroidal antiandrogens act as AF-1 agonists under conditions of high androgen-receptor expression.
BACKGROUND
The mechanism of resistance acquisition to antiandrogens in prostate cancer is not fully understood. Numerous clinical and basic research studies have shown expression of androgen receptors (ARs) increases in hormone-refractory prostate cancer and therefore we explored possible molecular mechanisms by which prostate cancer acquires resistance to antiandrogens under conditions of increased AR expression.


METHODS
In order to study resistance to antiandrogens at the AR transactivation level we used a human AR (hAR) reporter assay system. In addition, we utilized an hAR deletion mutant to determine the functional domain responsible for the acquisition of resistance.


RESULTS
Increased hAR protein expression enhanced the sensitivity of AR transactivation to low concentrations of DHT, and also reduced the inhibitory activity of the non-steroidal antiandrogens, hydroxyflutamide, and bicalutamide on DHT-induced AR transactivation. Moreover, these antiandrogens acquired agonistic activity under conditions of high hAR protein expression. Such agonistic activity of antiandrogens was not detected in an hAR deletion mutant (hAR-DeltaA/B) that lacked an A/B domain with AF-1 activity.


CONCLUSIONS
We found that non-steroidal antiandrogens act as AF-1 agonists under conditions of high AR protein expression. This partial antagonistic property of antiandrogens may be a molecular mechanism by which prostate cancer develops resistance to these drugs.
Fuse
Hiroaki
H
Pharmacological Research Department, ASKA Pharmaceutical Co. Ltd., Takatsu-ku, Kawasaki, Kanagawa, Japan. fuse-h@aska-pharma.co.jp
Korenaga
Shigeru
S
Sakari
Matomo
M
Hiyama
Takashi
T
Ito
Takeshi
T
Kimura
Koichi
K
Kato
Shigeaki
S
D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000819:agonists* / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*
C410798:AR protein, human; D000728:Androgens; D000813:Anilides; C086185:IFNGR2 protein, human; D009570:Nitriles; D011944:Receptors, Androgen; D017471:Receptors, Interferon; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D005485:Flutamide; C053541:bicalutamide