This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cheng, H. Articles by Rennie, P. S. Search for Related Content PubMed PubMed Citation Articles by Cheng, H. Articles by Rennie, P. S.

Short Hairpin RNA Knockdown of the Androgen Receptor Attenuates Ligand-Independent Activation and Delays Tumor Progression

The Prostate Center at Vancouver General Hospital and the Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Paul S. Rennie, The Prostate Center at Vancouver General Hospital and the Department of Surgery, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6. Phone: 604-875-4818; Fax: 604-875-5654; E-mail: prennie{at}interchange.ubc.ca.

Progression to androgen independence is the lethal end stage of prostate cancer. We used expression of androgen receptor (AR)-targeted short hairpin RNAs (shRNA) to directly test the requirement for AR in ligand-independent activation of androgen-regulated genes and hormone-independent tumor progression. Transient transfection of LNCaP human prostate cancer cells showed that AR shRNA decreased R1881 induction of the prostate-specific antigen (PSA)-luciferase reporter by 96%, whereas activation by forskolin, interleukin-6, or epidermal growth factor was inhibited 48% to 75%. Whereas the antiandrogen bicalutamide provided no further suppression, treatment with the mitogen-activated protein kinase (MAPK) inhibitor U0126 completely abrogated the residual activity, indicating a MAPK-dependent, AR-independent pathway for regulating the PSA promoter. Expression of doxycycline-inducible AR shRNA expression in LNCaP cells resulted in decreased levels of AR and PSA as well as reduced proliferation in vitro. When these cells were grown as xenografts in immunocompromised mice, induction of AR shRNA decreased serum PSA to below castration nadir levels and significantly retarded tumor growth over the entire 55-day experimental period. This is the first demonstration that, by inducibly suppressing AR expression in vivo, there is an extensive delay in progression to androgen independence as well as a dramatic inhibition of tumor growth and decrease in serum PSA, which exceeds that seen with castration alone. Based on these findings, we propose that suppressing AR expression may provide superior therapeutic benefit in reducing tumor growth rate than castration and may additionally be very effective in delaying progression to androgen independence. (Cancer Res 2006; 66(21): 10613-20)

This article has been cited by other articles:

				L. S. Lyons, S. Rao, W. Balkan, J. Faysal, C. A. Maiorino, and K. L. Burnstein Ligand-Independent Activation of Androgen Receptors by Rho GTPase Signaling in Prostate Cancer Mol. Endocrinol., March 1, 2008; 22(3): 597 - 608. [Abstract] [Full Text] [PDF]

				S. Papineni, S. Chintharlapalli, and S. Safe Methyl 2-Cyano-3,11-dioxo-18{beta}-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells Mol. Pharmacol., February 1, 2008; 73(2): 553 - 565. [Abstract] [Full Text] [PDF]

				S. M. Dehm and D. J. Tindall Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer Mol. Endocrinol., December 1, 2007; 21(12): 2855 - 2863. [Abstract] [Full Text] [PDF]

				S. Chouinard, O. Barbier, and A. Belanger UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells J. Biol. Chem., November 16, 2007; 282(46): 33466 - 33474. [Abstract] [Full Text] [PDF]

				J. T. Read, M. Rahmani, S. Boroomand, S. Allahverdian, B. M. McManus, and P. S. Rennie Androgen Receptor Regulation of the Versican Gene through an Androgen Response Element in the Proximal Promoter J. Biol. Chem., November 2, 2007; 282(44): 31954 - 31963. [Abstract] [Full Text] [PDF]