NDR1/FBXO11 promotes phosphorylation-mediated ubiquitination of (β-catenin to suppress metastasis in prostate cancer

Background: Prostate cancer progression hinges on beta-catenin's stability and activity, a key factor in epithelial-mesenchymal transition (EMT) and metastasis. This study delves into NDR1-dependent phosphorylation's impact on beta-catenin via FBXO11, an E3 ubiquitin ligase, in prostate cancer cells. Methods: Human prostate cancer cell lines underwent various in vitro assays, including real-time PCR, Western blotting, immunoprecipitation, immunofluorescence, and protein stability assays, to explore beta-catenin's interactions and post-translational modifications. NDR1 modulation's in vivo efficacy was assessed using a nude mice lung metastasis model. Small-molecule screening identified a potential NDR1 activator, aNDR1, tested for its effects on metastasis via in vitro and in vivo assays. Results: NDR1 phosphorylated beta-catenin at Ser33/37, facilitating its interaction with FBXO11. This led to FBXO11-mediated ubiquitination and cytoplasmic degradation of beta-catenin, while the NDR1-FBXO11 complex impeded beta-catenin nuclear translocation by inducing JNK2 ubiquitination. Thus, NDR1 and FBXO11 jointly regulate beta-catenin activity in prostate cancer cells through dual phosphorylation-driven ubiquitination, potentially suppressing EMT. Reduced NDR1 expression inhibited FBXO11 and beta-catenin phosphorylation, diminishing beta-catenin and JNK2 ubiquitination, promoting EMT and enhancing prostate cancer cell metastasis. The inhibitory effects of aNDR1 on prostate cancer metastasis were validated. Conclusion: The NDR1/FBXO11 axis outlines a non-canonical beta-catenin degradation pathway crucial in regulating EMT and prostate cancer cell metastasis. NDR1 activation, particularly with aNDR1, could offer a promising therapeutic avenue against prostate cancer metastasis.