Curcumin modulates β-catenin stabilization via targeting proteasomal deubiquitinating enzyme USP14☆

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research Pub Date : 2025-04-26 DOI:10.1016/j.phrs.2025.107745

Mengzhen Shen , Lizhe Chen , Jie Jiang, Ziye Wang, Qing Gong, Xue Zhang, Xisong Ke, Yi Qu

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引用次数: 0

Abstract

Loss of β-catenin homeostasis is tightly associated with human malignancies, modulation of β-catenin stabilization could be an attractive strategy for cancer therapy. In the present study, we demonstrated that an ancient drug curcumin was associated with selective accumulation of phosphorylated β-catenin (PBC) tagged with both ubiquitin (Ub) and Ub-like (Ubl) protein NEDD8. We further identified USP14, a deubiquitinating enzyme (DUB) in 19S proteasome, as a functional target of curcumin in modulating β-catenin. Curcumin enhances USP14-mediated PBC trapping and modulates proteasome associations, loss of USP14 significantly attenuated curcumin-increased PBC. Additionally, we found that USP14 deficiency suppressed mitotic entry and cell proliferation, targeting USP14 and PBC was essential for curcumin inhibition of cancer. Taken together, our study not only revealed the association of USP14 with PBC degradation within the proteasome, but also provided a unique small molecule curcumin targeting USP14 to modulate β-catenin for cancer therapy.

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姜黄素通过靶向蛋白酶体去泛素化酶USP14☆调节β-连环蛋白的稳定

β-catenin稳态的丧失与人类恶性肿瘤密切相关，调节β-catenin稳定可能是一种有吸引力的癌症治疗策略。在本研究中，我们证明了一种古老的药物姜黄素与磷酸化β-catenin （PBC）的选择性积累有关，PBC标记有泛素（Ub）和泛素样（Ubl）蛋白NEDD8。我们进一步确定了19S蛋白酶体中的去泛素化酶（DUB） USP14作为姜黄素调节β-连环蛋白的功能靶点。姜黄素增强了USP14介导的PBC捕获和调节蛋白酶体的关联，USP14的丢失显著减弱了姜黄素增加的PBC。此外，我们发现USP14缺陷抑制有丝分裂进入和细胞增殖，针对USP14和PBC是姜黄素抑制癌症的必要条件。综上所述，我们的研究不仅揭示了USP14与蛋白酶体内PBC降解的关联，而且提供了一种独特的小分子姜黄素靶向USP14调节β-catenin用于癌症治疗。

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

Pharmacological research 医学-药学

CiteScore

18.70

自引率

3.20%

发文量

491

审稿时长

8 days

期刊介绍： Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.