The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor.
Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.
Mizokami
Atsushi
A
Department of Urology, Kanazawa University, Kanazawa, Japan. mizokami@med.kanazawa-u.ac.jp
Koh
Eitetsu
E
Fujita
Hiroshi
H
Maeda
Yuji
Y
Egawa
Masayuki
M
Koshida
Kiyoshi
K
Honma
Seijiro
S
Keller
Evan T
ET
Namiki
Mikio
M
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000097:blood*; D015114:Androstenediol / Q000032:analysis*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017931:DNA Primers; D013196:Dihydrotestosterone / Q000097:blood; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics; D014162:Transfection
D000726:Androgen Antagonists; D000728:Androgens; D017931:DNA Primers; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015114:Androstenediol