Neuregulin induces prostate cancer cell migration via HER3/HER2-FAK/Src signaling axis

Neuregulin-1 β (NRG1) has emerged as a potential regulator of cancer cell migration, but its role in prostate cancer progression remains poorly understood. This study investigated the effects of NRG1 on prostate cancer cell behavior and elucidated the underlying molecular mechanisms. We examined NRG1 effects on cell migration and proliferation in three prostate cancer cell lines (PC-3, DU145, and LNCaP) using transwell migration assays. Protein-protein interactions were investigated using co-immunoprecipitation. Loss-of-function studies employed siRNA-mediated knockdown of key signaling components. Epithelial-mesenchymal transition (EMT) markers were assessed by Western blot analysis. Among the three cell lines tested, only DU145 cells showed enhanced migration in response to NRG1 treatment, which correlated with robust HER family receptor expression and functional HER3 phosphorylation. Specifically, HER3 knockdown completely abolished NRG1-induced migration and downstream signaling. Co-immunoprecipitation revealed that NRG1 specifically promotes HER3/HER2 heterodimerization and facilitates formation of a Src-centered signaling complex including FAK. Both FAK and Src were essential for NRG1-induced migration, as demonstrated by siRNA knockdown experiments. NRG1 treatment induced epithelial-mesenchymal transition characterized by dramatic Snail upregulation. This upregulation was dependent on the FAK/Src axis and GSK3β phosphorylation. NRG1 selectively promotes prostate cancer cell migration through a signaling cascade involving HER3/HER2 heterodimerization, FAK/Src activation, GSK3β phosphorylation, and Snail-mediated EMT. The cell line-specific response pattern suggests that neuregulin signaling may be relevant in specific prostate cancer subtypes characterized by particular receptor expression profiles. These findings provide mechanistic insight into NRG1-induced cell migration, reveal a partial EMT phenotype relevant to metastasis, and identify multiple potential therapeutic targets (HER3, FAK, Src, GSK3β) for inhibiting prostate cancer progression, particularly in castration-resistant prostate cancer subtypes.