In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors.
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.
Snoek
Robert
R
Prostate Center at Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
Cheng
Helen
H
Margiotti
Katia
K
Wafa
Latif A
LA
Wong
Charmaine A
CA
Wong
Erica Chan
EC
Fazli
Ladan
L
Nelson
Colleen C
CC
Gleave
Martin E
ME
Rennie
Paul S
PS
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
D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen