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Tissue Prostate-Specific Antigen Facilitates Refractory Prostate Tumor Progression via Enhancing ARA70-Regulated Androgen Receptor Transactivation

¹ George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, New York; ² Tianjin Institute of Urological Surgery, Tianjin Medical University, Tianjin, China; ³ Clinical Research Lab, Saad Specialist Hospital, Al-Khobar, Saudi Arabia; ⁴ Department of Urology, Zhejiang University and Hospital, Hangzhou, China; and ⁵ Department of Urology, Tzu Chi University, Hualien, Taiwan

Requests for reprints: Chawnshang Chang, George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642. Phone: 585-273-4500; Fax: 585-756-4133; E-mail: chang{at}urmc.rochester.edu.

Key Words: PSA • protease activity • p53 • prostate cancer xenograft

Despite being well recognized as the best biomarker for prostate cancer, pathophysiologic roles of prostate-specific antigen (PSA) remain unclear. We report here that tissue PSA may be involved in the hormone-refractory prostate cancer progression. Histologic analyses show that the increased tissue PSA levels are correlated with lower cell apoptosis index and higher cell proliferation rate in hormone-refractory tumor specimens. By stably transfecting PSA cDNA into various prostate cancer cell lines, we found that PSA could promote the growth of androgen receptor (AR)-positive CWR22rv1 and high-passage LNCaP (hormone-refractory prostate cancer cells) but not that of AR-negative PC-3 and DU145 cells. Surprisingly, the protease activity of PSA is not crucial for PSA to stimulate growth and promote AR transactivation. We further showed that increased PSA could enhance ARA70-induced AR transactivation via modulating the p53 pathway that results in the decreased apoptosis and increased cell proliferation in prostate cancer cells. Knockdown of PSA in LNCaP and CWR22rv1 cells causes cell apoptosis and cell growth arrest at the G₁ phase. In vitro colony formation assay and in vivo xenografted tumor results showed the suppression of prostate cancer growth via targeting PSA expression. Collectively, our findings suggest that, in addition to being a biomarker, PSA may also become a new potential therapeutic target for prostate cancer. PSA small interfering RNA or smaller molecules that can degrade PSA protein may be developed as alternative approaches to treat the prostate cancer. [Cancer Res 2008;68(17):7110–9]

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