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

作者：Xuezhen Yang, Min-Wei Chen, Stéphane Terry, Francis Vacherot, Dominique K. Chopin, Debra L. Bemis, Jan Kitajewski, Mitchell C. Benson, Yinglu Guo, Ralph O'Toole Buttyan · 发表于：Cancer Research · 年份：2005 · DOI：10.1158/0008-5472.can-05-0162 · 被引用次数：116 · 研究领域：Wnt/β-catenin signaling in development and cancer、Cancer-related gene regulation

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 beta-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear beta-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 beta-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 beta-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 beta-catenin, supporting the hypothe...