1. In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumours
- Author
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Robert Snoek, Erica Chan Wong, Martin E. Gleave, Helen Cheng, Colleen C. Nelson, Latif A. Wafa, Charmaine A. Wong, Ladan Fazli, Katia Margiotti, and Paul S. Rennie
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Transplantation, Heterologous ,Biology ,medicine.disease_cause ,Small hairpin RNA ,Mice ,chemistry.chemical_compound ,Prostate cancer ,Cell Line, Tumor ,Internal medicine ,Androgen Receptor Antagonists ,medicine ,Animals ,Humans ,Castration ,111201 Cancer Cell Biology ,Gene knockdown ,Prostatic Neoplasms ,Prostate-Specific Antigen ,medicine.disease ,111200 ONCOLOGY AND CARCINOGENESIS ,Androgen receptor ,Endocrinology ,Oncology ,chemistry ,Receptors, Androgen ,Tumor progression ,Gene Targeting ,Cancer cell ,Cancer research ,Androgen Independance, Castration-Resistant, Androgen Receptor, shRNA, Tumor Progression ,Growth inhibition ,Carcinogenesis ,060103 Cell Development Proliferation and Death - Abstract
Purpose: 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. Experimental Design: 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 mm3. 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.
- Published
- 2009