Pcdh-pc With Prostate Cancer Neuroendocrine Differentiation

Protocadherin-PC (PCDH-PC or PCDHY) is a gene product that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The gene encoding PCDH-PC lies on the human Y-chromosome in a region that was translocated from the X-chromosome during the evolutionary transition from primates to humans. Compared to its X-homologue, PCDH-PC has a small deletion in its coding sequence that removes the signal sequence and the product of this gene is cytoplasmically localized. PCDH-PC has a small serine-rich domain in its C-terminal region that is homologous to theβ-catenin binding site of classical cadherins. Hormone-resistant variants of prostate cancer cells that express PCDH-PC have high levels ofβ-catenin protein in their nuclear fractions consistent with evidence that these cells have increased wnt-signaling. In this study, we show that transfection of human prostate cancer, LNCaP, cells with PCDH-PC expression vecors or culture of LNCaP cells in androgenfree medium, an experimental condition that induces expression of PCDH-PC, activates wnt signaling in these cells as assessed by nuclear accumulation ofβ-catenin protein, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes such as c-myc, cyclin D and Cox-2. Moreover LNCaP cells transfected with the PCDH-PC expression vector or grown in androgen-free medium transdifferentiate to neuroendocrine- (NE-) like cells marked by elevated expression of neuron specific enolase and chromogranin-A and this NE transdifferentiation is also observed when LNCaP cells are transfected by a stabilizedβ-catenin expression vector. Increased wnt signaling and NE transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by effective siRNAs that target PCDH-PC as well as by dominant-negative Tcf or siRNA againstβ-catenin supporting the hypothesis that increased expression of PCDH-PC is driving the activation of wnt signaling and NE transdifferentiation by activating wnt signaling. These findings have significant implications for the understanding of the process through which prostate cancers progress to aggressive and hormone-resistant states in humans.