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

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zuodong Xuan, Chen Chen, Huimin Sun, Kunao Yang, Jinxin Li, Meilin Fu, Yang Bai, Zeyuan Zheng, Yue Zhao, Chunlan Xu, Bin Liu, Tian Li, Chen Shao
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引用次数: 0

Abstract

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./nMethods: 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./nResults: 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./nConclusion: 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.
NDR1/FBXO11 促进磷酸化介导的 β-catenin 泛素化,从而抑制前列腺癌的转移
背景:前列腺癌的进展取决于β-catenin的稳定性和活性,而β-catenin是上皮-间质转化(EMT)和转移的关键因素。本研究通过前列腺癌细胞中的E3泛素连接酶FBXO11,探讨了NDR1依赖性磷酸化对β-catenin的影响。方法:对人类前列腺癌细胞系进行各种体外检测,包括实时PCR、Western印迹、免疫沉淀、免疫荧光和蛋白质稳定性检测,以探讨β-catenin的相互作用和翻译后修饰。利用裸鼠肺转移模型评估了 NDR1 调节的体内疗效。小分子筛选确定了一种潜在的 NDR1 激活剂 aNDR1,并通过体外和体内试验测试了其对转移的影响:NDR1使β-catenin在Ser33/37处磷酸化,促进其与FBXO11的相互作用。这导致了 FBXO11 介导的 β-catenin 泛素化和胞质降解,而 NDR1-FBXO11 复合物通过诱导 JNK2 泛素化阻碍了 β-catenin 的核转位。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β-catenin的活性,从而可能抑制EMT。减少 NDR1 的表达可抑制 FBXO11 和 β-catenin 的磷酸化,减少 β-catenin 和 JNK2 的泛素化,促进 EMT 并增强前列腺癌细胞的转移。aNDR1对前列腺癌转移的抑制作用得到了验证:NDR1/FBXO11轴勾勒出了一条非经典β-catenin降解途径,对调控EMT和前列腺癌细胞转移至关重要。激活 NDR1(尤其是与 aNDR1 一起激活)可为前列腺癌转移提供一种前景广阔的治疗途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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