The invasive behaviour of prostatic cancer cells is suppressed by inhibitors of tyrosine kinase.
Proteolytic enzymes, and especially urokinase plasminogen activator (uPA), play an important role in tumour invasion and metastasis. Previously we demonstrated that the production of urokinase plasminogen activator (uPA) was decreased by several tyrosine kinase inhibitors (TKI) in two prostatic carcinoma cell lines. The effect of the two TKI genistein and tyrphostin AG-1478 was investigated in the prostate carcinoma cell lines PC-3 and DU-145. A reconstituted basal lamina (Matrigel) was used as a migration barrier. The production of matrix metalloproteinases (MMP) was also measured. Roles of plasminogen and uPA were examined. Cell invasion was increased by plasminogen, but this enhanced cell migration was counteracted by TKI treatment. The increased cell invasion induced by plasminogen was decreased by at least 60% in both cell lines when alpha-2 anti-plasmin was added to the assay. Cells in the absence of plasminogen were not affected by TKI. External uPA failed to regenerate the decreased cell invasion caused by TKI. The production of MMP was inhibited by both TKI. Our results indicate a possible role of TKI as inhibitors of cancer cell invasion by inhibiting uPA and MMP production.
Skogseth
Haakon
H
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. haakon.skogseth@ntnu.no
Larsson
Erik
E
Halgunset
Jostein
J
D001485:Basement Membrane / Q000737:chemistry / Q000473:pathology; D001681:Biological Assay; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010958:Plasminogen / Q000494:pharmacology; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011509:Proteoglycans / Q000737:chemistry; D011799:Quinazolines; D020032:Tyrphostins / Q000494:pharmacology*
D004338:Drug Combinations; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D011799:Quinazolines; D020032:Tyrphostins; C059485:matrigel; C101044:RTKI cpd; D010958:Plasminogen; D003094:Collagen; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D010960:Plasminogen Activators; D020782:Matrix Metalloproteinases