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Delta Tocotrienol Inhibits MMP‐9 Dependent Invasion and Metastasis of Non‐Small Cell Lung Cancer (NSCLC) Cell by Suppressing Notch‐1 Mediated NF‐κb and uPA Pathways
Author(s) -
Rajasinghe Lichchavi,
Pindiprolu Rohini,
Razalli Nurul,
Wu Yan,
Gupta Smiti
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.752.18
Subject(s) - cancer research , metastasis , mmp9 , notch signaling pathway , signal transduction , chemistry , cell migration , zymography , cell adhesion , biology , cell , matrix metalloproteinase , cancer , microbiology and biotechnology , downregulation and upregulation , biochemistry , gene , genetics
Delta‐tocotrienol (δT) has been shown to exhibit anti‐tumor activity via inhibition of different signaling pathways in tumors including NSCLC. Previously we showed that δT reduced cell invasion via inhibition of the Notch‐1 and NF‐κb pathway. Matrix metallopeptidase 9 (MMP9) dependent cell migration and invasion are key processes in cancer metastasis. Hence its suppression is a promising strategy for cancer therapeutics. The objective of this study was to investigate possibility of MMP9 inhibition as the underlying mechanism behind the anti‐metastatic effects of δT on NSCLC cell lines, A549 and H1299. Effect of δT on cell migration, invasion, cell‐adhesion and aggregation capability were investigated. MMP‐9 activity was determined using gel zymography. The various proteins, genes and miR involved in the Notch‐1 and uPA signal transduction pathways were investigated for anti‐metastatic activity by RT‐PCR and western blot. Our findings showed that δT reduced cell migration, invasion and adhesion in a dose and time dependent manner. δT significantly inhibited MMP‐9 activity in gel zymography. Further, δT inhibited Notch‐1 mediated NF‐κb and urokinase plasminogen activator (uPA) pathways which leads to down‐regulated expression of MMP‐9. Finally δT increased miR 451 and decreased miR 192 expressions, both of which have shown strong correlation with cell invasion and metastasis. Our data suggests that δT attenuates tumor aggressiveness, invasion and metastasis by down regulation of the MMP‐9 gene via Notch1 and uPA pathways. This warrants further investigation of δT as a potential natural therapeutic approach to prevent lung cancer invasion and metastasis.