Inhibitory effects of caffeic acid phenethyl ester on cancer cell metastasis mediated by the down-regulation of matrix metalloproteinase expression in human HT1080 fibrosarcoma cells

Caffeic acid phenethyl ester (CAPE) derived from honeybee propolis has been used as a folk medicine. Recent study also revealed that CAPE has several biological activities including antioxidation, anti-inflammation and inhibition of tumor growth. The present study investigated the effect of CAPE on tumor invasion and metastasis by determining the regulation of matrix metalloproteinases (MMPs). Matrix metalloproteinases, which are zinc-dependent proteolytic enzymes, play a pivotal role in tumor metastasis by cleavage of extracellular matrix (ECM) as well as nonmatrix substrates. On this line, we examined the influence of CAPE on the gene expression of MMPs (MMP-2, MMP-9, MT1-MMP), tissue inhibitor of metalloproteinase-2 (TIMP-2) and in vitro invasiveness of human fibrosarcoma cells. Dose-dependent decreases in MMP and TIMP-2 mRNA levels were observed in CAPE-treated HT1080 human fibrosarcoma cells as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Gelatin zymography analysis also exhibited a significant down-regulation of MMP-2 and MMP-9 expression in HT1080 cells treated with CAPE compared to controls. In addition, CAPE inhibited the activated MMP-2 activity as well as invasion, motility, cell migration and colony formation of tumor cells. These data therefore provide direct evidence for the role of CAPE as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of malignant cells.