In vitro inhibition of matriptase prevents invasive growth of cell lines of prostate and colon carcinoma

Int J Oncol. 2005 Oct;27(4):1061-70.


Matriptase, also known as membrane-type-serine-protease 1 (MT-SP 1), is a type II transmembrane serine protease involved in the activation of the precursor form of hepatocyte growth factor/scatter factor (pro-HGF/SF). Since HGF/SF is a well-known extracellular signal, which plays a key role in the control of invasive growth, we investigated the effects of matriptase inhibition in cell lines derived from colon (DLD-1) or prostate (PC-3) carcinomas. Biochemical analysis showed that matriptase was very efficient in the proteolytic conversion of the inactive HGF/SF precursor into HGF/SF. Inhibition of endogenous matriptase synthesis in DLD-1 or PC-3 cells by specific small interfering RNAs impaired the conversion of pro-HGF/SF into HGF/SF at the cell surface and inhibited cell scattering upon pro-HGF/SF stimulation. The same effect was observed after treatment of these cells with matriptase inhibitors of the 3-amidinophenylalanine-type, CJ-697 or CJ-730. Inhibition of matriptase significantly reduced invasion of the extracellular matrix as well. Interestingly, this reduction was observed even in the presence of pre-activated HGF/SF. It is concluded that matriptase plays a dual-role in the events unleashing the invasive phenotype, one 'upstream' from the HGF/SF signalling cascade and one 'downstream', most likely at the level of the plasminogen activation system. These data provide a proof of concept for the targeting of matriptase in the search for anti-invasive drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Proliferation
  • Collagen / chemistry
  • Colonic Neoplasms / drug therapy*
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • In Vitro Techniques
  • Inhibitory Concentration 50
  • Kinetics
  • Laminin / chemistry
  • Male
  • Models, Chemical
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Peptide Hydrolases / chemistry
  • Phenylalanine / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Protein Precursors / metabolism
  • Protein Structure, Tertiary
  • Proteoglycans / chemistry
  • RNA, Small Interfering / metabolism
  • Serine Endopeptidases / metabolism*
  • Signal Transduction
  • Time Factors


  • Drug Combinations
  • Enzyme Inhibitors
  • Laminin
  • Protein Precursors
  • Proteoglycans
  • RNA, Small Interfering
  • pro-hepatocyte growth factor
  • matrigel
  • Phenylalanine
  • Hepatocyte Growth Factor
  • Collagen
  • Peptide Hydrolases
  • Serine Endopeptidases
  • matriptase