Metastasis is one of the main causes of death for patients with malignant tumors. Aberrant expression of matrix metalloproteinase-9 (MMP-9) has been implicated in the invasion and metastasis of various cancer cells. Here we found CADPE (caffeic acid 3,4-dihydroxy -phenethyl ester) could inhibit the migration and invasion of human gastric carcinoma cells in transwell migration assays. To understand the underlying mechanism, we demonstrated that CADPE significantly inhibited PMA-induced increases in MMP-9 expression and activity in a dose-dependent manner. The inhibitory effect of CADPE on MMP-9 expression correlated well with the suppression of MMP-9 promoter activity and the reduction of MMP-9 mRNA. Reporter gene assay and electrophoretic mobility shift assay demonstrated that CADPE inhibited MMP-9 expression by suppressing the activation of the nuclear transcription factor activator protein-1 (AP-1) and c-Fos, but not NF-κB. Moreover, CADPE can inhibit PMA-induced phosphorylation of protein kinases involved in AP-1 activation, such as FAK, MEK, ERK1/2, whereas CADPE has little effect on the phosphorylation of p38 and JNK. Together, our findings indicate that CADPE could be a unique anti-tumor agent that specifically inhibits MMP-9 activity by targeting the activation of FAK/MEK/ERK protein kinases and AP-1 transcription factor.
- Received March 22, 2010.
- Revision received September 3, 2010.
- Accepted September 5, 2010.
- Copyright © 2010, American Association for Cancer Research.