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

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-kappa B (NF-kappa B) 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-kappa B nuclear translocation and I kappa B alpha 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-delta pathway. In conclusion, we demonstrated that the anti-invasive effects of bergamottin might occur through inhibition of protein kinase C-delta, p38 mitogen-activated protein kinase, and JNK phosphorylation and reduction of NF-kappa B 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.