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

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

  • Phytomedicine. 2025 Apr:139:156468. doi: 10.1016/j.phymed.2025.156468.
Guo-Sheng Lin 1,  Rou-Qiao Zheng 1,  Zi-Wei Xu 1,  Shang-Ping Xing 2,  Hui-Fei Wu 3,  Youliang Xie 4,  Huicai Huang 5,  Yong-Qiang Liu 6
Affiliations

Affiliations

  • 1 Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China.
  • 2 Pharmaceutical College, Guangxi Medical University, Nanning 530021, China.
  • 3 Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan 528400, China.
  • 4 Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: [email protected].
  • 5 Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. Electronic address: [email protected].
  • 6 Research Center of Chinese Herbal Resource Science and Engineering, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. Electronic address: [email protected].
PMID: 39978271 DOI: 10.1016/j.phymed.2025.156468
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.

Keywords

Brusatol; Epithelial-mesenchymal transition; Non-small cell lung cancer; TGF-β signaling; TGFβRII; Tumor metastasis.

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