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Carcinogenesis Advance Access published online on November 16, 2007
Carcinogenesis, doi:10.1093/carcin/bgm261
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-{kappa}B and AP-1

Chia-Jui Weng1, Chi-Fai Chau1, Yih-Shou Hsieh2, Shun-Fa Yang3 and Gow-Chin Yen1,*

1 Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan
2 Institute of Biochemistry and Biotechnology, Chung Shang Medical University, Taichung, Taiwan
3 Institute of Medicine, Chung Shang Medical University, Taichung, Taiwan

* Author to whom correspondence should be addressed., Tel: 886-4-2287-9755, Fax: 886-4-2285-4378, e-mail: gcyen{at}nchu.edu.tw

Ganoderma lucidum has been reported to be associated with suppressed motility, invasion and metastasis of several types of cancers, but its mechanism of action remains unclear. In our previous study, lucidenic acids A, B, C and N were isolated from a new strain of G. lucidum and all of them were found to have potential anti-invasive activity on phorbol-12-myristate-13-acetate (PMA)-induced HepG2 cells by suppressing the matrix metalloproteinase (MMP)-9 activity. Here, the lucidenic acid B was used to explore its mechanisms underlying MMP-9 expression of HepG2 cells. The results showed that the lucidenic acid B suppressed PMA-induced MMP-9 activity in a dose-dependent transcriptional level. The suppression of PMA-induced MMP-9 expression of HepG2 cells by lucidenic acid B was through inactivating phosphorylation of ERK1/2. The treatment of MEK inhibitors (PD98059 and U0126) and lucidenic acid B to HepG2 cells could result in a synergistic reduction on the MMP-9 expression along with an inhibition on cell invasion. Moreover, lucidenic acid B also strongly inhibited PMA-stimulated nuclear factor-kappa B (NF-{kappa}B) and activator protein-1 (AP-1) DNA binding activities of HepG2 cells in dose-dependent manners. A dose-dependent inhibition on protein levels of NF-{kappa}B, c-Jun and c-Fos in nuclear by lucidenic acid B treatment was further observed. In conclusion, we demonstrated that the anti-invasive effects of the lucidenic acid B on the PMA-induced HepG2 cells might be through inhibiting the phosphorylation of ERK1/2 and reducing AP-1 and NF-{kappa}B DNA binding activities, leading to down-regulation of MMP-9 expression.

Key Words: lucidenic acid • invasion • HepG2 cells • MMP-9 • NF-{kappa}B • AP-1

Received September 10, 2007; revised November 9, 2007; accepted November 9, 2007.


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