title: 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.
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-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.
authors: College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors: Yong Pil
authors: YP
authors: Hwang
authors: Hyo Jeong
authors: HJ
authors: Yun
authors: Jae Ho
authors: JH
authors: Choi
authors: Keon Wook
authors: KW
authors: Kang
authors: Hye Gwang
authors: HG
authors: Jeong
mesh_terms: 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
chemical_list: 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