Proteomic screening identifies brusatol targets TGFβRII to suppresses non-small cell lung cancer metastasis

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL Phytomedicine Pub Date : 2025-02-11 DOI:10.1016/j.phymed.2025.156468

Guo-Sheng Lin , Rou-Qiao Zheng , Zi-Wei Xu , Shang-Ping Xing , Hui-Fei Wu , Youliang Xie , Huicai Huang , Yong-Qiang Liu

{"title":"Proteomic screening identifies brusatol targets TGFβRII to suppresses non-small cell lung cancer metastasis","authors":"Guo-Sheng Lin , Rou-Qiao Zheng , Zi-Wei Xu , Shang-Ping Xing , Hui-Fei Wu , Youliang Xie , Huicai Huang , Yong-Qiang Liu","doi":"10.1016/j.phymed.2025.156468","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Metastasis remains the leading cause of cancer mortality. The natural product brusatol (Bru) has exhibited promising anticancer activity; however, the target proteins of Bru and the underlying mechanisms in suppressing tumor metastasis remain unclear.</div></div><div><h3>Purpose</h3><div>We aim to identify the target of Bru and examine its role in suppressing tumor metastasis.</div></div><div><h3>Methods</h3><div>The human proteome microarrays and biotin-labelled Bru were employed to identify the direct targets of Bru. To evaluate the anti-migration properties of Bru, <em>TGF-β1</em> overexpressing NSCLC cells were constructed, wound-healing and transwell assays were performed. The anti-metastatic effects of Bru were assessed using A549-luciferase cell orthotopic xenografts.</div></div><div><h3>Results</h3><div>We identified that Bru has a high binding affinity for the TGF-β receptor type-II (TGFβRII) protein by probing biotin-labelled Bru on human proteome microarrays. Bru can directly interact with TGFβRII and then effectively suppress recombinant TGF-β1- or <em>TGF-β1</em> overexpression-induced phosphorylation of Smad2 and Smad3, leading to reduced expression of epithelial-mesenchymal transition (EMT)-associated proteins and the suppression of NSCLC cell migration and invasion. Furthermore, Bru suppressed TGF-β signaling and exerted anti-metastatic activity in the orthotopic xenografts using A549-luciferase cells overexpressing <em>TGF-β1</em>.</div></div><div><h3>Conclusion</h3><div>Our findings identified that Bru functions as a novel TGFβRII inhibitor, leading to the abrogation of TGF-β signaling activation and the suppression of NSCLC metastasis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"139 ","pages":"Article 156468"},"PeriodicalIF":6.7000,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711325001096","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Metastasis remains the leading cause of cancer mortality. The natural product brusatol (Bru) has exhibited promising anticancer activity; however, the target proteins of Bru and the underlying mechanisms in suppressing tumor metastasis remain unclear.

Purpose

We aim to identify the target of Bru and examine its role in suppressing tumor metastasis.

Methods

The human proteome microarrays and biotin-labelled Bru were employed to identify the direct targets of Bru. To evaluate the anti-migration properties of Bru, TGF-β1 overexpressing NSCLC cells were constructed, wound-healing and transwell assays were performed. The anti-metastatic effects of Bru were assessed using A549-luciferase cell orthotopic xenografts.

Results

We identified that Bru has a high binding affinity for the TGF-β receptor type-II (TGFβRII) protein by probing biotin-labelled Bru on human proteome microarrays. Bru can directly interact with TGFβRII and then effectively suppress recombinant TGF-β1- or TGF-β1 overexpression-induced phosphorylation of Smad2 and Smad3, leading to reduced expression of epithelial-mesenchymal transition (EMT)-associated proteins and the suppression of NSCLC cell migration and invasion. Furthermore, Bru suppressed TGF-β signaling and exerted anti-metastatic activity in the orthotopic xenografts using A549-luciferase cells overexpressing TGF-β1.

Conclusion

Our findings identified that Bru functions as a novel TGFβRII inhibitor, leading to the abrogation of TGF-β signaling activation and the suppression of NSCLC metastasis.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

求助全文

约1分钟内获得全文去求助

来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.