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Departments of ¹ Urology and ² Molecular and Integrative Physiology; ³ Kansas Masonic Cancer Research Institute; and ⁴ Landon Center on Aging, University of Kansas Medical Center, Kansas City, Kansas

Requests for reprints: Benyi Li, Department of Urology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. Phone: 913-588-4773; Fax: 913-588-4756. E-mail: bli{at}kumc.edu

Prostate cancer is the second leading cause of cancer death in the United States and, thus far, there has been no effective therapy for the treatment of hormone-refractory disease. Recently, the androgen receptor (AR) has been shown to play a critical role in the development and progression of the disease. In this report, we showed that knocking down the AR protein level by a small interfering RNA (siRNA) approach resulted in a significant apoptotic cell death as evidenced by an increased annexin V binding, reduced mitochondrial potential, caspase-3/6 activation, and DFF45 and poly(ADP-ribose) polymerase cleavage. The apoptotic response was specifically observed in those siRNA-transfected cells that harbor a native AR gene. No cell death was found in the AR-null prostate cancer cell PC-3 or its subline that has been reconstituted with an exogenous AR gene, as well as two breast cancer cell lines that are AR positive. Moreover, in parallel with the siRNA-induced AR silencing, the antiapoptotic protein Bcl-xL was significantly reduced, which might account for the apoptotic cell death because ectopic enforced expression of Bcl-xL protein partially inhibited apoptosis after AR silencing. Taken together, our data showed that knocking down the AR protein level in prostate cancer cells leads to apoptosis by disrupting the Bcl-xL–mediated survival signal downstream of AR-dependent survival pathway.

Key Words: androgen receptor • apoptosis • gene silencing • prostate cancer • RNA interference • small interfering RNA

Grant support: KU William L. Valk Endowment, Kansas Mason's Foundation, Department of Defense Prostate Cancer Research Program grant DAMD17-03-1-0121, and Southwest Oncology Group HOPE Foundation (B. Li).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Unpublished observation.

Received 11/23/04; revised 1/19/05; accepted 2/17/05.

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