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Updated: Jun 27, 2025
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Verteporfin inhibits TGF-β signaling by disrupting the Smad2/3-Smad4 interaction
Junxiu Nong1, Shengqiang Shen2, Fan Hong3
1The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Abstract:
Transforming growth factor-β (TGF-β) signaling plays a crucial role in pathogenesis, such as accelerating tissue fibrosis and promoting tumor development at the later stages of tumorigenesis by promoting epithelial-mesenchymal transition (EMT), cancer cell migration, and invasion. Targeting TGF-β signaling is a promising therapeutic approach, but nonspecific inhibition may result in adverse effects. In this study, we focus on the Smad2/3-Smad4 complex, a key component in TGF-β signaling transduction, as a potential target for cancer therapy. Through a phase-separated condensate-aided biomolecular interaction system, we identified verteporfin (VP) as a small-molecule inhibitor that specifically targets the Smad2/3-Smad4 interaction. VP effectively disrupted the interaction between Smad2/3 and Smad4 and thereby inhibited canonical TGF-β signaling, but not the interaction between Smad1 and Smad4 in bone morphogenetic protein (BMP) signaling. Furthermore, VP exhibited inhibitory effects on TGF-β-induced EMT and cell migration. Our findings indicate a novel approach to develop protein-protein interaction inhibitors of the canonical TGF-β signaling pathway for treatments of related diseases.
Insights
Verteporfin (VP) specifically inhibits the Smad2/3-Smad4 interaction, a key part of transforming growth factor-β (TGF-β) signaling. This targeted approach offers a new strategy for cancer therapy by disrupting TGF-β-induced cell changes.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor-β (TGF-β) signaling is implicated in fibrosis and cancer progression via epithelial-mesenchymal transition (EMT), migration, and invasion.
- Nonspecific inhibition of TGF-β signaling can lead to adverse effects, necessitating targeted therapeutic strategies.
Purpose of the Study:
- To identify a specific inhibitor of the Smad2/3-Smad4 complex, a critical mediator of canonical TGF-β signaling, for potential cancer therapy.
- To evaluate the efficacy of identified inhibitors in disrupting TGF-β signaling and its downstream effects.
Main Methods:
- Utilized a phase-separated condensate-aided biomolecular interaction system to screen for inhibitors.
- Tested identified small molecules for their ability to specifically disrupt the Smad2/3-Smad4 interaction.
- Assessed the impact of the inhibitor on TGF-β-induced EMT and cell migration.
Main Results:
- Identified verteporfin (VP) as a small-molecule inhibitor that specifically targets the Smad2/3-Smad4 interaction.
- VP disrupted the Smad2/3-Smad4 complex, inhibiting canonical TGF-β signaling without affecting Smad1-Smad4 interaction in bone morphogenetic protein (BMP) signaling.
- VP demonstrated inhibitory effects on TGF-β-induced EMT and cancer cell migration.
Conclusions:
- Verteporfin (VP) is a specific inhibitor of the Smad2/3-Smad4 interaction, offering a targeted approach to modulate TGF-β signaling.
- This study presents a novel strategy for developing protein-protein interaction inhibitors for treating TGF-β-related diseases, including cancer.
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