In vitro inhibition of matriptase prevents invasive growth of cell lines of prostate and colon carcinoma.
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.
Förbs
Diana
D
Curacyte AG, D-80339 Munich, Germany.
Thiel
Stefan
S
Stella
Maria C
MC
Stürzebecher
Anne
A
Schweinitz
Andrea
A
Steinmetzer
Torsten
T
Stürzebecher
Jörg
J
Uhland
Kerstin
K
D015153:Blotting, Western; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007797:Laminin / Q000737:chemistry; D008297:Male; D008956:Models, Chemical; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010447:Peptide Hydrolases / Q000737:chemistry; D010649:Phenylalanine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011498:Protein Precursors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D011498:Protein Precursors; D011509:Proteoglycans; D034741:RNA, Small Interfering; C086013:pro-hepatocyte growth factor; C059485:matrigel; D010649:Phenylalanine; D017228:Hepatocyte Growth Factor; D003094:Collagen; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases; C485595:matriptase