Relaxin drives Wnt signaling through upregulation of PCDHY in prostate cancer

BACKGROUND. Relaxin, a potent peptide hormone of the insulin-like family normally produced and secreted by the human prostate, is upregulated in castrate resistant prostate cancer progression. In various tissues, relaxin increases angiogenesis and cell motility through upregulation of vascular endothelial growth factor, matrix metalloproteases, and nitric oxide, and therefore maybe an attractive target for cancer therapeutics. METHODS. To examine the role of relaxin in prostate cancer progression, LNCaP cells stably transfected with relaxin (LNCaP_RLN) were used to form xenograft tumors, and microarray expression analysis was subsequently performed to determine novel pathways regulated by relaxin. Prostate cancer tissue microarrays from patient samples were stained by immunohistochemistry for further validation and correlation of the findings. RESULTS. Expression analysis identified novel relaxin regulated pathways, including the ProtocadherinY (PCDHY)/Wnt pathway. PCDHY, which upregulates Wnt11, has previously been shown to stabilize b-catenin, causing b-catenin to translocate from the cytoplasmic membrane to the nucleus and initiate TCF-mediated signaling. LNCaPRLN xenografts exhibit increased PCDHY expression and increased cytoplasmic localization of b-catenin, suggesting relaxin directs Wnt11 overexpression through PCDHY upregulation. Similarly, prostate cancer samples from patients who have undergone androgen ablation have increased Wnt11 expression, which is further upregulated in castrate resistant tissues. Like relaxin, Wnt11, and PCDHY are negatively regulated by androgens, and further analysis indicated that the overexpression of relaxin results in dysregulation of androgen-regulated genes. CONCLUSIONS. These data suggest that prostate cancer cell motility and altered androgen receptor activity attributed to relaxin may be mediated in part by Wnt11.