Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by bergamottin via the inhibition of protein kinase Cdelta/p38 mitogen-activated protein kinase and JNK/nuclear factor-kappaB-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-kappaB (NF-kappaB) 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-kappaB nuclear translocation and IkappaBalpha 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-kappaB 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.
Hwang
Yong Pil
YP
College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
Yun
Hyo Jeong
HJ
Choi
Jae Ho
JH
Kang
Keon Wook
KW
Jeong
Hye Gwang
HG
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D015536:Down-Regulation / Q000187:drug effects; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011564:Furocoumarins / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D011564:Furocoumarins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; C016658:phorbolol myristate acetate; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C068337:bergamottin; D013755:Tetradecanoylphorbol Acetate