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

• Published in: Acta pharmacologica Sinica Vol. 41; no. 5; pp. 698 - 705
• Main Authors: Zhang, Le-le, Guo, Jing, Jiang, Xiao-Ming, Chen, Xiu-Ping, Wang, Yi-Tao, Li, Ao, Lin, Li-Gen, Li, Hua, Lu, Jin-Jian
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.05.2020; Springer Singapore
• Subjects: A549 Cells; Activating Transcription Factor 4 - antagonists & inhibitors; Activating Transcription Factor 4 - biosynthesis; Activating Transcription Factor 4 - genetics; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Antitumor activity; Cell Proliferation - drug effects; Computational Biology; Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Diterpenes; Diterpenes - administration & dosage; Diterpenes - isolation & purification; Diterpenes - pharmacology; Drug Screening Assays, Antitumor; Humans; Injections, Intraperitoneal; Lung cancer; Male; Mice; Mice, SCID; Molecular Docking Simulation; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - genetics; Podocarpus; Protein biosynthesis; Protein synthesis; Protein Synthesis Inhibitors - administration & dosage; Protein Synthesis Inhibitors - isolation & purification; Protein Synthesis Inhibitors - pharmacology; Proteins; Ribonucleic acid; RNA; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - biosynthesis; STAT3 Transcription Factor - genetics; Tumor Cells, Cultured; Xenografts; human lung cancer A549 cell line xenograft; Click-iT; diterpenoids; molecular docking; RNA-seq; CMap; RIOK2; nagilactone E; protein synthesis inhibitor
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0332-7

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 ·d , 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.