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Phytomedicine. 2019 Jan;52:32-39. doi: 10.1016/j.phymed.2018.09.222. Epub 2018 Sep 26.

Nagilactone E suppresses TGF-β1-induced epithelial-mesenchymal transition, migration and invasion in non-small cell lung cancer cells.

Author information

1
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
2
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China.
4
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: LigenL@umac.mo.
5
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: jinjianlu@umac.mo.

Abstract

BACKGROUND:

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death around the world. Epithelial-mesenchymal transition (EMT) has been documented to increase motility and invasiveness of cancer cells, which promotes cancer metastasis.

PURPOSE:

This study aims to investigate the inhibitory effects and mechanisms of the dinorditerpenoids and norditerpenoids isolated from the seeds of Podocarpus nagi against transforming growth factor (TGF)-β1-induced EMT.

METHODS:

A series of dinorditerpenoids and norditerpenoids were isolated from the seeds of P. nagi. Western blot and quantitative real-time PCR assays were performed to determine the expression levels of relative proteins and mRNA, along with immunofluorescence, Smad-binding element (SBE)-luciferase and chromatin immunoprecipitation (ChIP) assays for the mechanism study. Transwell assays were conducted to determine the effect of the compounds on cell migration and invasion.

RESULTS:

Nagilactone E (NLE) showed the superior inhibitory effect against TGF-β1-induced EMT. NLE treatment dramatically inhibited TGF-β1-induced expression of EMT markers in A549 cells. Mechanism study indicated that NLE markedly suppressed TGF-β1-induced Smad2 and Smad3 activation and nuclear translocation. SBE-luciferase and ChIP assays showed that NLE inhibited the combining of Smad3 to SBE in the promoters of the cell signaling factors. NLE co-treatment attenuated TGF-β1-induced up-regulation of the protein and mRNA levels of TGF-β receptor TβRI. Furthermore, NLE inhibited TGF-β1-stimulated cell migration and invasion, as well as up-regulation of the key signaling proteins related with migration and invasion.

CONCLUSION:

NLE inhibited TGF-β/Smad signaling pathway, thereafter suppressed TGF-β1-induced EMT, migration and invasion in NSCLC A549 cells.

KEYWORDS:

Epithelial-mesenchymal transition; Nagilactone E; Smad; TGF-β1

PMID:
30599910
DOI:
10.1016/j.phymed.2018.09.222
[Indexed for MEDLINE]

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