Abstract
Wnt/beta-Catenin signaling plays a critical role in prostate cancer (PCa) progression, yet its precise contributions in neuroendocrine prostate cancer (NEPCa) remain incompletely understood. In this study, we utilized TRAMP/Wnt-reporter mice to monitor Wnt/beta-Catenin activity and investigated transcriptional alterations associated with NEPCa development. RNA sequencing and pathway enrichment analyses identified neuroactive ligand-receptor interaction, MAPK, calcium, and cAMP signaling as key pathways enriched in NEPCa. Although Wnt signaling was not among the top-enriched pathways, elevated Axin2 expression and increased Wnt-reporter activity suggest its involvement in NEPCa progression. We observed upregulated expression of Wnt3, Wnt6, Dvl2, Dvl3, and Lef1 in NEPCa, coupled with reduced expression of Yap1 and Frat1, which are involved in beta-Catenin degradation. Pharmacological inhibition of Wnt/beta-Catenin signaling using FC101 significantly suppressed PCa growth, underscoring its potential as a therapeutic target. These findings reveal that Wnt/beta-Catenin signaling is active in NEPCa through multiple mechanisms and highlight the need for further investigation into the regulatory interplay between Wnt and YAP1 in prostate cancer.