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Published on: September 13, 2018
The natural compound codonolactone impairs tumor induced angiogenesis by downregulating BMP signaling in endothelial
Shan Wang1, Rui Cai1, Junchao Ma1
1Department of Pharmacology, School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
Background:
Angiogenesis, the recruitment of new blood vessels, was demonstrated that is an essential component of the growth of a tumor beyond a certain size and the metastatic pathway. The potential use of angiogenesis-based agents, such as those involving natural and synthetic inhibitors as anticancer drugs is currently under intense investigation. In this study, the anti-angiogenic properties of codonolactone (CLT), a sesquiterpene lactone from Atractylodes lancea, were examined in endothelial cells.
Purpose:
Our published study reported that CLT shows significant anti-metastatic properties in vitro and in vivo. In order to determine whether angiogenic-involved mechanisms contribute to the anti-metastatic effects of CLT, we checked the anti-angiogenic properties of CLT and its potential mechanisms.
Study Design/Methods:
Human umbilical vein endothelial cells (HUVECs) and EA.hy 926 cells were involved in this study. Immunofluorescence assay for cells and immunohistochemistry assay for tissues were used to check the expression of angiogenic markers. In vitro migration and invasion of endothelial cells treated with and without CLT were analyzed. Protein expressions were measured by Western blot analysis. For MMPs activity assay, fluorescence resonance energy transfer-based MMPs activity assay and gelatin zymography assay were involved in this study.
Results:
Here we demonstrated that CLT exhibited inhibition on cancer cell induced angiogenesis in vivo, and direct inhibited migration and invasion of endothelial cells in vitro. Moreover, we observed that the down-regulation of MMPs and VEGF-VEGFR2 was involved in the anti-angiogenic effects of CLT. Data from Western blotting showed that, in endothelial cells, CLT reduced Runx2 activation and BMP signaling.
Conclusion:
Our findings demonstrated that CLT impaired the development of angiogenesis both in vitro and in vivo by direct inhibition on endothelial cells. These inhibitory effects were depended on its ability to interference with BMP signaling in endothelial cells, which may cause inhibition of MMPs expression and VEGF secretion by down-regulating Runx2 activation.
Insights
Codonolactone (CLT) inhibits angiogenesis by directly acting on endothelial cells, suppressing migration and invasion. This anti-angiogenic effect is mediated by interfering with BMP signaling, down-regulating Runx2 activation, MMPs, and VEGF.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Angiogenesis is crucial for tumor growth and metastasis.
- Angiogenesis inhibitors are a key area of anticancer drug research.
- Codonolactone (CLT), a sesquiterpene lactone, is investigated for its anti-angiogenic properties.
Purpose of the Study:
- To investigate the anti-angiogenic properties of codonolactone (CLT).
- To determine if CLT's anti-metastatic effects involve anti-angiogenic mechanisms.
- To elucidate the potential mechanisms underlying CLT's anti-angiogenic activity.
Main Methods:
- Assessed angiogenesis markers using immunofluorescence and immunohistochemistry.
- Analyzed endothelial cell migration and invasion in vitro.
- Measured protein expression via Western blot.
- Quantified matrix metalloproteinases (MMPs) activity using FRET and zymography.
Main Results:
- CLT inhibited cancer cell-induced angiogenesis in vivo and endothelial cell migration/invasion in vitro.
- CLT down-regulated matrix metalloproteinases (MMPs) and VEGF-VEGFR2 signaling.
- CLT reduced Runx2 activation and BMP signaling in endothelial cells.
Conclusions:
- CLT impairs angiogenesis in vitro and in vivo by directly inhibiting endothelial cells.
- CLT's anti-angiogenic effects stem from interference with BMP signaling.
- This interference involves down-regulating Runx2 activation, leading to reduced MMPs expression and VEGF secretion.
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