布鲁斯他汀通过调节miR-574-5p/USP10/PLK1轴抑制胶质瘤的恶性进展。

Brusatol suppresses malignant progression of glioma via modulating the miR-574-5p/USP10/PLK1 axis.

作者信息

Ma Binbin, Wang Lei, Li Jian, Zhang Borui, Wang Yichuan, Li Na, Shen Dachuan, Han Chuanchun

机构信息

The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116044, China.

Institute of Cancer Stem Cells, Dalian Medical University, Dalian, Liaoning 116044, China.

出版信息

Phytomedicine. 2025 Oct;146:157142. doi: 10.1016/j.phymed.2025.157142. Epub 2025 Aug 6.

DOI:10.1016/j.phymed.2025.157142

PMID:40779822

Abstract

BACKGROUND

Brusatol (BRU), a compound derived from Brucea javanica, has demonstrated notable antitumour activity across various cancer types. However, its precise mechanisms and functional roles in glioma remain incompletely understood.

PURPOSE

To explore the role and downstream target of Brusatol in glioma and uncover the potential molecular mechanism.

STUDY DESIGN

In vitro and in vivo experiments using glioma cell lines, as well as quantitative proteomics were performed to explore the role and downstream target of Brusatol.

METHODS

Cell growth and apoptosis were investigated by colony formation and propidium iodide (PI) staining assays, respectively. Quantitative proteomics was performed to identify altered proteins in glioma cells upon treatment with different concentrations of Brusatol. The effects of ubiquitin-specific peptidase 10 (USP10) on polo-like kinase 1 (PLK1) expression were investigated by western blotting and co-immunoprecipitation (Co-IP) assays. The relationship between USP10 and miRNA-574-5p was assessed by luciferase assay and western blotting.

RESULTS

In this study, we observed that Brusatol inhibited glioma cell proliferation and migration and promoted apoptosis in vitro, as well as suppressed tumour formation in vivo. Mechanistic investigations revealed that Brusatol markedly downregulated the expression of PLK1. Notably, elevated PLK1 levels attenuated the antitumour efficacy of Brusatol in LN229 and U251 cells. Furthermore, our results indicated that USP10 interacted with PLK1, suppressing its degradation and thereby counteracting the antitumour effects of Brusatol. Additionally, our data also demonstrated that miR-574-5p is significantly upregulated upon Brusatol treatment. Elevated miR-574-5p reduced USP10 expression, enhancing the inhibitory effects of Brusatol on glioma cells.

CONCLUSION

Collectively, these findings indicate that the miR-574-5p/USP10/PLK1 axis plays a pivotal role in mediating the antitumour effects of Brusatol and may have potential clinical implications for glioma therapy.

摘要

背景

鸦胆子苦醇（BRU）是一种从鸦胆子中提取的化合物，已在多种癌症类型中显示出显著的抗肿瘤活性。然而，其在胶质瘤中的精确机制和功能作用仍不完全清楚。

目的

探讨鸦胆子苦醇在胶质瘤中的作用和下游靶点，揭示潜在的分子机制。

研究设计

使用胶质瘤细胞系进行体外和体内实验，并进行定量蛋白质组学研究，以探讨鸦胆子苦醇的作用和下游靶点。

方法

分别通过集落形成和碘化丙啶（PI）染色试验研究细胞生长和凋亡。进行定量蛋白质组学以鉴定不同浓度鸦胆子苦醇处理后胶质瘤细胞中发生变化的蛋白质。通过蛋白质印迹法和免疫共沉淀（Co-IP）试验研究泛素特异性肽酶10（USP10）对polo样激酶1（PLK1）表达的影响。通过荧光素酶试验和蛋白质印迹法评估USP10与miRNA-574-5p之间的关系。

结果

在本研究中，我们观察到鸦胆子苦醇在体外抑制胶质瘤细胞增殖和迁移并促进凋亡，在体内抑制肿瘤形成。机制研究表明，鸦胆子苦醇显著下调PLK1的表达。值得注意的是，PLK1水平升高减弱了鸦胆子苦醇对LN229和U251细胞的抗肿瘤功效。此外，我们的结果表明，USP10与PLK1相互作用，抑制其降解，从而抵消鸦胆子苦醇的抗肿瘤作用。此外，我们的数据还表明，鸦胆子苦醇处理后miR-574-5p显著上调。miR-574-5p升高降低了USP10的表达，增强了鸦胆子苦醇对胶质瘤细胞的抑制作用。