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Proteomic screening identifies brusatol targets TGFβRII to suppresses non-small cell lung cancer metastasis
Guo-Sheng Lin1, Rou-Qiao Zheng1, Zi-Wei Xu1
1Research 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.
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.
Insights
The natural compound brusatol (Bru) inhibits the TGF-beta receptor type-II (TGFβRII), blocking cancer cell migration and metastasis in non-small cell lung cancer (NSCLC). This discovery offers a potential new strategy for treating metastatic cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastasis is the primary cause of cancer-related deaths.
- Brusatol (Bru), a natural product, shows anticancer potential, but its targets and mechanisms against metastasis are unknown.
Purpose of the Study:
- To identify brusatol's protein targets.
- To investigate brusatol's role in suppressing tumor metastasis.
Main Methods:
- Human proteome microarrays and biotinylated brusatol identified direct targets.
- Non-small cell lung cancer (NSCLC) cells overexpressing TGF-β1 were used to assess anti-migration.
- Wound-healing, transwell, and orthotopic xenograft assays evaluated anti-metastatic effects.
Main Results:
- Brusatol directly binds to TGF-beta receptor type-II (TGFβRII).
- Brusatol inhibits TGF-β signaling by suppressing Smad2/3 phosphorylation, reducing epithelial-mesenchymal transition (EMT) markers, and inhibiting NSCLC cell migration and invasion.
- Brusatol demonstrated anti-metastatic activity in vivo.
Conclusions:
- Brusatol acts as a novel inhibitor of TGFβRII.
- Brusatol abrogates TGF-β signaling, suppressing NSCLC metastasis.
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