Document Detail


The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor.
MedLine Citation:
PMID:  14744796     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Atsushi Mizokami; Eitetsu Koh; Hiroshi Fujita; Yuji Maeda; Masayuki Egawa; Kiyoshi Koshida; Seijiro Honma; Evan T Keller; Mikio Namiki
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  64     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-27     Completed Date:  2004-04-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  765-71     Citation Subset:  IM    
Affiliation:
Department of Urology, Kanazawa University, Kanazawa, Japan. mizokami@med.kanazawa-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Androgen Antagonists / therapeutic use*
Androgens / blood*
Androstenediol / analysis*
Cell Division / drug effects
Cell Line, Tumor
DNA Primers
Dihydrotestosterone / blood
Genes, Reporter
Humans
Male
Mutation
Polymerase Chain Reaction
Prostatic Hyperplasia / drug therapy
Prostatic Neoplasms / chemistry*,  drug therapy,  genetics,  pathology
Receptors, Androgen / drug effects*,  genetics
Transfection
Chemical
Reg. No./Substance:
0/Androgen Antagonists; 0/Androgens; 0/DNA Primers; 0/Receptors, Androgen; 521-17-5/Androstenediol; 521-18-6/Dihydrotestosterone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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