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A Human- and Male-Specific Protocadherin that Acts through the Wnt Signaling Pathway to Induce Neuroendocrine Transdifferentiation of Prostate Cancer Cells

¹ Department of Urology, First Hospital, Peking University, Beijing, China; Departments of ² Urology, and ³ Pathology, Columbia University Medical Center, New York, New York; and ⁴ Institut National de la Sante et de la Recherche Medicale, Department of Urology, Université Paris XII, CHU Henri Mondor, Assistance Publique des Hôpitaux de Paris, Créteil, France

Requests for reprints: Ralph Buttyan, Department of Urology, Columbia University Medical Center, Irving Pavilion-11, 161 Fort Washington Avenue, New York, NY 10032. Phone: 212-305-1574; Fax: 212-305-1564; E-mail: rb46{at}columbia.edu.

Protocadherin-PC (PCDH-PC)is a gene on the human Y chromosome that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the ß-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear ß-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of ß-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized ß-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against ß-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans.

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