Abstract
Metastasis causes the main lethality in esophageal cancer patient. Garcinol, a natural compound extracted from Gambogic genera, is a histone acetyltransferase (HAT) inhibitor that has shown anticancer activities such as cell cycle arrest and apoptosis induction. In this study, we investigated the effects of garcinol on the metastasis of esophageal cancer in vitro and in vivo. We found that garcinol (5–15 μM) dose-dependently inhibited the migration and invasion of human esophageal cancer cell lines KYSE150 and KYSE450 in wound healing, transwell migration, and Matrigel invasion assays. Furthermore, garcinol treatment dose-dependently decreased the protein levels of p300/CBP (transcriptional cofactors and HATs) and p-Smad2/3 expression in the nucleus, thus impeding tumor cell proliferation and metastasis. Knockdown of p300 could inhibit cell metastasis, but CBP knockdown did not affect the cell mobility. It has been reported that TGF-β1 stimulated the phosphorylation of Smad2/3, which directly interact with p300/CBP in the nucleus, and upregulating HAT activity of p300. We showed that garcinol treatment dose-dependently suppressed TGF-β1-activated Smad and non-Smad pathway, inhibiting esophageal cancer cell metastasis. In a tail vein injection pulmonary metastasis mouse model, intraperitoneal administration of garcinol (20 mg/kg) or 5-FU (20 mg/kg) significantly decreased the number of lung tumor nodules and the expression levels of Ki-67, p300, and p-Smad2/3 in lung tissues. In conclusion, our study demonstrates that garcinol inhibits esophageal cancer metastasis in vitro and in vivo, which might be related to the suppression of p300 and TGF-β1 signaling pathways, suggesting the therapeutic potential of Garcinol for metastatic tumors.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (Nos. 81773951 and 81303188) and the three-year development plan project for Traditional Chinese Medicine (ZY(2018-2020)-CCCX-2001-02) to HXX.
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JW and MW contributed equally. Study concept and design: YZL, HXX and JW; chemical synthesis and micelle characterization: DZ, HZ and HST; biological study: JW, MW and LZ; analysis of data: JW, MW, HZ, and YL; drafting of the manuscript: JW and MW.
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Wang, J., Wu, M., Zheng, D. et al. Garcinol inhibits esophageal cancer metastasis by suppressing the p300 and TGF-β1 signaling pathways. Acta Pharmacol Sin 41, 82–92 (2020). https://doi.org/10.1038/s41401-019-0271-3
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DOI: https://doi.org/10.1038/s41401-019-0271-3
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