Suppression of PMA-induced tumor cell invasion and metastasis by aqueous extract isolated from Prunella vulgaris via the inhibition of NF-kappaB-dependent MMP-9 expression

Abstract

Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. In this study, we examined the inhibitory effects of tumor cell migration and invasion by aqueous extract isolated from Prunella vulgaris (PVAE) using in vitro and in vivo assays. PVAE reduced PMA-induced activation of MMP-9 and further inhibited cell invasion and migration. PVAE suppressed PMA-enhanced expression of MMP-9 protein, mRNA and transcription activity levels through suppression of NF-kappaB activation without changing the tissue inhibitor of metalloproteinase level. PVAE inhibited PMA-induced NF-kappaB nuclear translocation, which is upstream of PMA-induced MMP-9 expression and invasion. Furthermore, pretreatment with NF-kappaB activation inhibitor inhibited the PMA-induced MMP-9 expression and activity. PVAE repressed the PMA-induced phosphorylation of ERK1/2, which is upstream signaling molecules in MMP-9 expression. We confirmed that the inhibitory effect of PVAE on lung metastasis and tumor cell growth using B16-F10 melanoma cells or B16-F1 melanoma cells in C57BL/6 mice. The oral administrations of PVAE reduced the lung metastasis and tumor cell growth by B16-F10 or B16-F1 melanoma cells. These results suggested that the anti-metastatic effect of PVAE is mediated through the suppression of MMP-9 expression by the inhibition of NF-kappaB via ERK1/2 signaling pathway as well as MMP-9 activity.