Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of NF-κB, uPA activator, and MMP-9
Received 18 December 2017
Accepted for publication 20 April 2018
Published 24 July 2018 Volume 2018:11 Pages 4301—4314
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Ashok Kumar Pandurangan
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Geoffrey Pietersz
Lichchavi D Rajasinghe, Rohini H Pindiprolu, Smiti Vaid Gupta
Department of Nutrition and Food Science, Wayne State University, Detroit, MI, USA
Background: Delta-tocotrienol (δT), an isomer of vitamin E, exhibits anticancer properties in different cancer types including non-small-cell lung cancer (NSCLC). Yet, anti-invasive effects of δT and its underlying cellular mechanism in NSCLC have not been fully explored. Matrix metalloproteinase 9 (MMP-9)-based cell migration and invasion are critical cellular mechanisms in cancer development. The current evidence indicates that MMP-9 is upregulated in most patients, and the inhibition of MMPs is involved in decreasing invasion and metastasis in NSCLC. Therefore, its suppression is a promising strategy for attenuating cell invasion and metastasis processes in NSCLC.
Purpose: The aim of this study was to evaluate the possibility of MMP-9 inhibition as the underlying mechanism behind the antimetastatic properties of δT on NSCLC cells.
Methods: The effects of δT on cell proliferation, migration, invasion, adhesion, and aggregation capabilities were investigated using different cell-based assays. An inhibitory effect of MMP-9 enzyme activity with δT was also identified using gel zymography. Using real-time PCR and Western blot analysis, a number of cellular proteins, regulatory genes, and miRNA involved in the Notch-1 and urokinase-type plasminogen activator (uPA)-mediated MMP-9 pathways were examined.
Results: The study found that δT inhibited cell proliferation, cell migration, invasion, aggregation, and adhesion in a concentration-dependent manner and reduced MMP-9 activities. Real-time PCR and Western blot analysis data revealed that δT increased miR-451 expressions and downregulated Notch-1-mediated nuclear factor-κB (NF-κB), which led to the repressed expression of MMP-9 and uPA proteins.
Conclusion: δT attenuated tumor invasion and metastasis by the repression of MMP-9/uPA via downregulation of Notch-1 and NF-κB pathways and upregulation of miR-451. The data suggest that δT may have potential therapeutic benefit against NSCLC metastasis.
Keywords: metalloproteinases, miR-451, lung cancer, A549, H1299, metastasis, cell migration, vitamin E
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