Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by bergamottin via the inhibition of protein kinase Cδ/p38 mitogen-activated protein kinase and JNK/nuclear factor-κB-dependent matrix metalloproteinase-9 expression

Abstract

Matrix metalloproteinase (MMP) plays an important role in the invasion and metastasis of cancer cells. The inhibitory effects of bergamottin, a cytochrome P450 inhibitor from Citrus paradis (grapefruit), on tumor invasion and migration and the possible mechanisms involved in this inhibition were investigated in human fibrosarcoma HT‐1080 cells. Bergamottin reduced phorbol‐12‐myristate‐13‐acetate (PMA)‐induced activation of MMP‐9 and MMP‐2 and further inhibited cell invasion and migration. Bergamottin suppressed PMA‐enhanced expression of MMP‐9 protein, mRNA and transcription activity levels through suppression of nuclear factor‐κB (NF‐κB) activation without changing the tissue inhibitor of metalloproteinase 1 level. Bergamottin also reduced PMA‐enhanced MMP‐2 expression through suppression of membrane‐type 1 MMP, but did not alter tissue inhibitor of metalloproteinase 2 levels. Bergamottin inhibited PMA‐induced NF‐κB nuclear translocation and IκBα degradation, which are upstream of PMA‐induced MMP‐9 expression and invasion. Furthermore, bergamottin strongly repressed the PMA‐induced phosphorylation of p38 mitogen‐activated protein kinase and c‐Jun N‐terminal kinase (JNK), which are dependent on the protein kinase C‐δ pathway. In conclusion, we demonstrated that the anti‐invasive effects of bergamottin might occur through inhibition of protein kinase C‐δ, p38 mitogen‐activated protein kinase, and JNK phosphorylation and reduction of NF‐κB activation, leading to downregulation of MMP‐9 expression. These results suggest that the suppression of MMP expression contributes, at least in part, to the antitumor activity of bergamottin.