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

Toxicol Lett. 2011 May 30;203(1):9-19. doi: 10.1016/j.toxlet.2011.02.013. Epub 2011 Feb 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Benzodioxoles / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Fibrosarcoma / enzymology*
  • Fibrosarcoma / genetics
  • Fibrosarcoma / pathology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Phosphorylation
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / pharmacology*
  • Protein Kinase C-alpha / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Time Factors
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic / drug effects
  • Transfection


  • Alkaloids
  • Antineoplastic Agents, Phytogenic
  • Benzodioxoles
  • NF-kappa B
  • Piperidines
  • Polyunsaturated Alkamides
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • PRKCA protein, human
  • Protein Kinase C-alpha
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Matrix Metalloproteinase 9
  • Tetradecanoylphorbol Acetate
  • piperine