Abstract
Norditerpenoids and dinorditerpenoids represent diterpenoids widely distributed in the genus Podocarpus with notable chemical structures and biological activities. We previously reported that nagilactone E (NLE), a dinorditerpenoid isolated from Podocarpus nagi, possessed anticancer effects against lung cancer cells in vitro. In this study we investigated the in vivo effect of NLE against lung cancer as well as the underlying mechanisms. We administered NLE (10 mg·kg−1·d−1, ip) to CB-17/SCID mice bearing human lung cancer cell line A549 xenograft for 3 weeks. We found that NLE administration significantly suppressed the tumor growth without obvious adverse effects. Thereafter, RNA sequencing (RNA-seq) analysis was performed to study the mechanisms of NLE. The effects of NLE on A549 cells have been illustrated by GO and pathway enrichment analyses. CMap dataset analysis supported NLE to be a potential protein synthesis inhibitor. The inhibitory effect of NLE on synthesis of total de novo protein was confirmed in Click-iT assay. Using the pcDNA3-RLUC-POLIRES-FLUC luciferase assay we further demonstrated that NLE inhibited both cap-dependent and cap-independent translation. Finally, molecular docking revealed the low-energy binding conformations of NLE and its potential target RIOK2. In conclusion, NLE is a protein synthesis inhibitor with anticancer activity.
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Acknowledgements
This work was supported by the Science and Technology Development Fund, Macau SAR (File no. 176/2017/A3), and the Research Fund of the University of Macau (MYRG2018-00165-ICMS, CPG2019-00006-ICMS, and MYRG2015-00153-ICMS-QRCM). We thank Prof. Yun Tang (East China University of Science and Technology) for his kindly help with this work.
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LLZ and JJL designed this study. LGL provided the compound NLE. LLZ and JG performed the experiments. LLZ, HL and JJL drafted the paper. LLZ, XMJ, HL and JJL analyzed the data. All the authors participated in the revision and improvement of the paper.
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Zhang, Ll., Guo, J., Jiang, Xm. et al. Identification of nagilactone E as a protein synthesis inhibitor with anticancer activity. Acta Pharmacol Sin 41, 698–705 (2020). https://doi.org/10.1038/s41401-019-0332-7
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DOI: https://doi.org/10.1038/s41401-019-0332-7
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