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Published on: October 27, 2020
Natural alkaloid 8-oxo-epiberberine inhibited TGF-β1-triggred epithelial-mesenchymal transition by interfering Smad3
Xin Liu1, Yiying Zhang1, Guang-Ju Zhou2
1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
Abstract:
Epithelial-mesenchymal transition (EMT), the transition of epithelial cells into mesenchymal cells, plays important roles in the metastasis of solid tumors. 8-Oxo-epiberberine (OPB) is a natural alkaloid extracted from the roots of Coptis chinensis Franch. In this study, The effect and the underlying mechanism of OPB on EMT in a TGF-β1-induced model and the inhibitory effect of OPB on lung metastasis were investigated. TGF-β1-stimulated lung cancer cells were co-treated with OPB, the morphological changes were examined. The protein expression of EMT biomarkers E-cadherin and N-cadherin was determined by Western blotting and immunofluorescence. The transcription activity of smad2/3 promoter was analyzed by a luciferase reporter assay. The effect of OPB on cell migration, invasion, and adhesion was detected by wound-healing, adhesion, and transwell assays. The in vivo anti-metastatic effect of OPB was evaluated using a 4 T1 cell xenograft mouse model. Results showed that OPB significantly reversed TGF-β1-triggered morphological changes, expression of EMT biomarkers, and migration, adhesion, and invasion. Furthermore, OPB suppressed TGF-β1-induced Smad2/3 activation, Smad3 phosphorylation and nuclear translocation, and interaction of Smad3 with Smad4. Besides, OPB dramatically decreased the metastatic nodules in the lung without affecting the growth of primary tumors. In conclusion, OPB inhibited TGF-β1-induced EMT possibly by interfering with Smad3. OPB might have therapeutic potentials for the treatment of metastatic cancers.
Insights
8-Oxo-epiberberine (OPB) inhibits epithelial-mesenchymal transition (EMT), a key process in cancer metastasis. This natural compound suppressed lung metastasis in vivo by interfering with the Smad3 signaling pathway, suggesting therapeutic potential.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Epithelial-mesenchymal transition (EMT) is crucial for solid tumor metastasis.
- Understanding EMT's mechanisms is vital for developing anti-metastatic therapies.
Purpose of the Study:
- To investigate the effect of 8-Oxo-epiberberine (OPB) on TGF-β1-induced EMT in lung cancer cells.
- To elucidate the underlying molecular mechanism of OPB's action.
- To evaluate OPB's efficacy in inhibiting lung metastasis in vivo.
Main Methods:
- TGF-β1-induced EMT model in lung cancer cells.
- Western blotting and immunofluorescence for EMT biomarkers (E-cadherin, N-cadherin).
- Luciferase reporter assay for Smad2/3 promoter activity.
- Cell migration, invasion, and adhesion assays.
- 4T1 cell xenograft mouse model for in vivo anti-metastatic evaluation.
Main Results:
- OPB reversed TGF-β1-induced morphological changes and EMT biomarker expression.
- OPB significantly inhibited cell migration, invasion, and adhesion.
- OPB suppressed TGF-β1-induced Smad2/3 activation, Smad3 phosphorylation, nuclear translocation, and Smad3/Smad4 interaction.
- OPB reduced lung metastatic nodules in vivo without affecting primary tumor growth.
Conclusions:
- OPB effectively inhibits TGF-β1-induced EMT, likely by interfering with the Smad3 signaling pathway.
- OPB demonstrates significant anti-metastatic potential in preclinical models.
- OPB shows promise as a therapeutic agent for metastatic cancers.
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