Article

Identification of nagilactone E as a protein synthesis inhibitor with anticancer activity

Authors: Le-le Zhang1,2, Jing Guo3, Xiao-ming Jiang1, Xiu-ping Chen1, Yi-tao Wang1, Ao Li4, Li-gen Lin1, Hua Li3, Jin-jian Lu1
1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2 School of Medicine, Chengdu University, Chengdu 610106, China
3 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
4 College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 401331, China
Correspondence to: Li-gen Lin: LigenL@um.edu.mo, Hua Li: li_hua@hust.edu.cn, Jin-jian Lu: jinjianlu@um.edu.mo,
DOI: 10.1038/s41401-019-0332-7
Received: 13 August 2019
Accepted: 8 November 2019
Advance online: 11 February 2020

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.
Keywords: nagilactone E; diterpenoids; human lung cancer A549 cell line xenograft; RNA-seq; CMap; Click-iT; molecular docking; RIOK2; protein synthesis inhibitor

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