Abstract
Vanillin has been reported to exhibit anti-invasive and antimetastatic activities by suppressing the enzymatic activity of matrix metalloproteinase-9 (MMP-9). However, the underlying mechanism of anti-invasive activity remains unclear so far. Herein we demonstrate that vanillin reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 gelatinolytic activity and suppressed cell invasion through the down-regulation of MMP-9 gene transcription in HepG2 cells. Vanillin significantly reduced the 6.6-fold invasive capacity of HepG2 cells in noncytotoxic concentrations, and this anti-invasive effect was concentration-dependent in the Matrigel invasion assay. Moreover, vanillin significantly suppressed the TPA-induced enzymatic activity of MMP-9 and decreased the induced mRNA level of MMP-9. Analysis of the transcriptional regulation indicated that vanillin suppressed MMP-9 transcription by inhibiting nuclear factor-κB (NF-κB) activity. Western blot further confirmed that vanillin inhibited NF-κB activity through the inhibition of IκB-α phosphorylation and degradation. In conclusion, vanillin might be a potent antiinvasive agent that suppresses the MMP-9 enzymatic activity via NF-κB signaling pathway.
Footnotes
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This work was supported by grants from National Research Program for Genomic Medicine, National Science and Technology Program for Agricultural Biotechnology, National Science Council, Committee on Chinese Medicine and Pharmacy, Department of Health (CCMP 96-RD-201 and CCMP 97-RD-201), and China Medical University, Taiwan.
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C.-Y.H. and T.-Y.H. contributed equally to this work.
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ABBREVIATIONS: MMP, matrix metalloproteinase; AP-1, activator protein 1; DMEM, Dulbecco's modified Eagle's medium; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HCC, hepatocellular carcinoma; MMP-9, matrix metalloproteinase-9; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NF-κB, nuclear factor-κB; RLU, relative luciferase unit; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; TPA, 12-O-tetradecanoylphorbol-13-acetate.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received June 6, 2008.
- Accepted October 1, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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