Matrix metalloproteinases (
MMPs),
zinc-dependent
proteolytic enzymes, play a pivotal role in
tumor metastasis by cleavage of extracellular matrix as well as non-matrix substrates. In this study, we examined the influence of
DA-125, a new anthracyclin analog, on the gene expression of
MMPs (MMP-2, MMP-9 and MT1-MMP),
tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and in vitro invasiveness of human
fibrosarcoma cells. Dose-dependent decreases of
MMPs and TIMPs
mRNA levels were observed in DA-125-treated HT1080 human
fibrosarcoma cells detected by
reverse transcriptase-polymerase chain reaction.
Gelatin zymography analysis also showed a significant down-regulation of MMP-2 and MMP-9 expression in HT1080 cells treated with
DA-125 compared to controls. In addition,
DA-125 inhibited the invasion, motility and cell migration, and colony formation of
tumor cells. These data, therefore, provide direct evidence for the role of
DA-125 as a potential
cancer chemotherapeutic agent, which can markedly inhibit the invasive capacity of malignant cells. Further, to clarify the transcriptional regulatory pathway, we primarily investigated the role of
nuclear factor-kappaB (
NF-kappaB) in the expression of
MMPs by
DA-125 in HT1080 cells. Electrophoretic mobility shift assay demonstrated that
DA-125 modulates the binding activity of
NF-kappaB. Using the
luciferase reporter gene assay, a dose-dependent down-regulation of
NF-kappaB-mediated
luciferase expression was also observed. These results suggest that
DA-125 down-regulates
MMPs expression in HT1080 cells through the
NF-kappaB-mediated pathway.