title: In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors.
abstract: OBJECTIVE
  Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors.
  
  
  METHODS
  Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) were generated to directly test the effects of AR knockdown in C4-2 human prostate cancer cells and tumors.
  
  
  RESULTS
  In vitro expression of AR shRNA resulted in decreased levels of AR mRNA and protein, decreased expression of prostate-specific antigen (PSA), reduced activation of the PSA-luciferase reporter, and growth inhibition of C4-2 cells. Gene microarray analyses revealed that AR knockdown under hormone-deprived conditions resulted in activation of genes involved in apoptosis, cell cycle regulation, protein synthesis, and tumorigenesis. To ensure that tumors were truly castration-resistant in vivo, inducible AR shRNA expressing C4-2 tumors were grown in castrated mice to an average volume of 450 mm(3). In all of the animals, serum PSA decreased, and in 50% of them, there was complete tumor regression and disappearance of serum PSA.
  
  
  CONCLUSIONS
  Whereas castration is ineffective in castration-resistant prostate tumors, knockdown of AR can decrease serum PSA, inhibit tumor growth, and frequently cause tumor regression. This study is the first direct evidence that knockdown of AR is a viable therapeutic strategy for treatment of prostate tumors that have already progressed to the castration-resistant state.
authors.affiliation: Prostate Center at Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoek
authors.forename: Helen
authors.initials: H
authors.lastname: Cheng
authors.forename: Katia
authors.initials: K
authors.lastname: Margiotti
authors.forename: Latif A
authors.initials: LA
authors.lastname: Wafa
authors.forename: Charmaine A
authors.initials: CA
authors.lastname: Wong
authors.forename: Erica Chan
authors.initials: EC
authors.lastname: Wong
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D018390:Gene Targeting; D006801:Humans; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen