title: Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by piperine via the inhibition of PKCα/ERK1/2-dependent matrix metalloproteinase-9 expression.
abstract: Piperine is a major component of black pepper, Piper nigrum Linn, used widely in traditional medicine. Several previous studies reported that piperine possesses various beneficial biological activities including antioxidant, anti-tumor and anti-inflammation properties. In the present study, we investigated the inhibitory effects of piperine on tumor invasion and migration and the possible mechanisms involved using human fibrosarcoma HT-1080 cells. We found that piperine suppresses PMA-enhanced matrix metalloproteinase-9 (MMP-9) expression at the protein, mRNA, and transcriptional levels through the suppression of NF-κB and AP-1 activation without changing the level of tissue inhibitor of metalloproteinase (TIMP)-1. Piperine also inhibits PMA-enhanced membrane-type 1 MMP expression without changing the level of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Piperine inhibited PMA-induced NF-κB and c-Jun nuclear translocation, which are upstream of PMA-induced MMP-9 expression and invasion. Furthermore, piperine strongly repressed the PMA-induced phosphorylation of ERK, which are dependent on the PKCα pathway. In conclusion, we demonstrated that the anti-invasive effects of piperine may occur through inhibition of PKCα and ERK phosphorylation and reduction of NF-κB and AP-1 activation, leading to down-regulation of MMP-9 expression. Thus, piperine has potential as a potent anti-cancer drug in therapeutic strategies for fibrosarcoma metastasis.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Yong Pil
authors.initials: YP
authors.lastname: Hwang
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Yun
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Han
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Chung
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005354:Fibrosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D052117:Benzodioxoles; D016328:NF-kappa B; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; C008922:piperine