背景：前列腺癌的进展取决于β-连环蛋白的稳定性和活性，β-连环蛋白是上皮间质转化（EMT）和转移的关键因素。这项研究深入探讨了前列腺癌细胞中 NDR1 依赖性磷酸化通过 FBXO11（一种 E3 泛素连接酶）对 β-连环蛋白的影响。方法：对人前列腺癌细胞系进行各种体外测定，包括实时 PCR、蛋白质印迹、免疫沉淀、免疫荧光和蛋白质稳定性测定，以探索 β-catenin 的相互作用和翻译后修饰。使用裸鼠肺转移模型评估 NDR1 调节的体内功效。小分子筛选确定了一种潜在的 NDR1 激活剂 aNDR1，并通过体外和体内测定测试了其对转移的影响。结果：NDR1 在 Ser33/37 位点磷酸化 β-连环蛋白，促进其与 FBXO11 的相互作用。这导致 FBXO11 介导的 β-catenin 泛素化和细胞质降解，而 NDR1-FBXO11 复合物通过诱导 JNK2 泛素化阻碍 β-catenin 核转位。因此，NDR1 和 FBXO11 通过双重磷酸化驱动的泛素化共同调节前列腺癌细胞中的 β-catenin 活性，从而可能抑制 EMT。 NDR1 表达减少会抑制 FBXO11 和 β-catenin 磷酸化，减少 β-catenin 和 JNK2 泛素化，促进 EMT 并增强前列腺癌细胞转移。验证了aNDR1对前列腺癌转移的抑制作用。结论：NDR1/FBXO11 轴勾勒出一条非经典的 β-连环蛋白降解途径，对于调节 EMT 和前列腺癌细胞转移至关重要。 NDR1 激活，特别是 aNDR1，可以提供一种有前景的对抗前列腺癌转移的治疗途径。© 作者。

Background: Prostate cancer progression hinges on β-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 β-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 β-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 β-catenin at Ser33/37, facilitating its interaction with FBXO11. This led to FBXO11-mediated ubiquitination and cytoplasmic degradation of β-catenin, while the NDR1-FBXO11 complex impeded β-catenin nuclear translocation by inducing JNK2 ubiquitination. Thus, NDR1 and FBXO11 jointly regulate β-catenin activity in prostate cancer cells through dual phosphorylation-driven ubiquitination, potentially suppressing EMT. Reduced NDR1 expression inhibited FBXO11 and β-catenin phosphorylation, diminishing β-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 β-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.© The author(s).