title: Androgen receptor or estrogen receptor-beta blockade alters DHEA-, DHT-, and E(2)-induced proliferation and PSA production in human prostate cancer cells.
abstract: BACKGROUND
  Dehydroepiandrosterone (DHEA) is an endogenous steroid that is metabolized to androgens and/or estrogens in the human prostate. DHEA levels decline with age, and use of DHEA supplements to retard the aging process is of unproved effectiveness and safety. LNCaP and LAPC-4 prostate cancer cells were used to determine whether DHEA-modulated proliferation and prostate specific antigen (PSA) production were mediated via the androgen receptor (AR) and/or ERbeta.
  
  
  METHODS
  Cells were treated with DHEA, DHT, or E(2) and antagonists to AR (Casodex-bicalutamide) or ER (ICI 182,780) or siRNA to the respective receptors. Proliferation was assessed by MTT assay and PSA mRNA and protein secretion were measured by quantitative real-time PCR and ELISA. Associations of AR and ERbeta were analyzed by co-immunoprecipitation studies and fluorescent confocal microscopy.
  
  
  RESULTS
  DHEA-, T-, and E(2)-induced proliferation of LNCaP cells was blunted by Casodex but not by ICI treatment. In LNCaP cells, Casodex and ICI suppressed hormone-induced PSA production. In LAPC-4 cells, DHT-stimulated PSA mRNA was inhibited by Casodex and ICI, and the minimal stimulation by DHEA was inhibited by ICI. Use of siRNAs confirmed involvement of AR and ERbeta in hormone-induced PSA production while AR-ERbeta co-association was suggested by immunoprecipitation and nuclear co-localization.
  
  
  CONCLUSIONS
  These findings support involvement of both AR and ERbeta in mediating DHEA-, DHT-, and E(2)-induced PSA expression in prostate cancer cells.
authors.affiliation: Endocrine Section, Laboratory of Clinical Investigation, Division of Intramural Research, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892-0933, USA. jarnold@mail.nih.gov
authors.forename: Julia T
authors.initials: JT
authors.lastname: Arnold
authors.forename: Xunxian
authors.initials: X
authors.lastname: Liu
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Allen
authors.forename: Hanh
authors.initials: H
authors.lastname: Le
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: McFann
authors.forename: Marc R
authors.initials: MR
authors.lastname: Blackman
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077267:Fulvestrant; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000502:physiology; D013739:Testosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D009570:Nitriles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D000077267:Fulvestrant; D013739:Testosterone; D003687:Dehydroepiandrosterone; D004958:Estradiol; C013915:boldenone; C053541:bicalutamide; D017430:Prostate-Specific Antigen