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The Nuclear Factor-B Pathway Controls the Progression of Prostate Cancer to Androgen-Independent Growth

¹ Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, ² Department of Cancer Biology, and ³ Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; ⁴ Department of Urology, Konkuk University Hospital, Seoul, Korea; ⁵ Departments of Medicine, Urology, and Molecular and Medical Pharmacology, University of California, Los Angeles, California; and ⁶ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York

Requests for reprints: Robert J. Matusik, Vanderbilt Prostate Cancer Center and Department of Urologic Surgery, Vanderbilt University Medical Center, A1329 MCN, 1161 21st Avenue South, Nashville, TN 37232-2765. Phone: 615-343-1902; Fax: 615-322-8990; E-mail: robert.matusik{at}vanderbilt.edu.

Key Words: NF-B • Prostate Cancer • Androgen Independent

Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" stage that results in renewed growth and spread of the cancer. Both nuclear factor-B (NF-B) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-B pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-B signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-B signaling in vivo by the absence of the IB inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-B pathway was activated in the ARR₂PB-myc-PAI (Hi-myc) mouse prostate by cross-breeding into a IB^+/– haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-B is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-B pathway may be a potential target for therapy against androgen-independent prostate cancer. [Cancer Res 2008;68(16):6762–9]

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