Inhibitors of tyrosine kinase inhibit the production of urokinase plasminogen activator in human prostatic cancer cells.
Urokinase-type plasminogen activator (uPA) seems to be an important protease in prostate cancer invasion, and tyrosine phosphorylation is thought to play a role in the regulation of its production. The amount of uPA was measured with a synthetic peptide substrate after treatment with various concentrations of tyrosine kinase inhibitors (TKI). The effect on proliferation and apoptosis was also assayed. Non-toxic levels of genistein or the tyrphostin AG 490 produced up to 50% reduction of the uPA production in PC-3 and DU-145. The tyrphostins AG 1296 and AG 1478 inhibited uPA production in PC-3 cells, whereas DU-145 showed a slight increase of uPA production. TKI neither induced any detectable apoptosis, nor was there any reduction in proliferation rate. TKI can profoundly modify the production of uPA in prostatic cancer cells, thus indicating their possible use as suppressors of the invasive phenotype. The therapeutic potential of TKI warrants further investigation.
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
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C106250:6,7-dimethoxy-3-phenylquinoxaline; C101044:RTKI cpd; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D014568:Urokinase-Type Plasminogen Activator