Urokinase plasminogen activator receptor (uPAR) expression is reduced by tyrosine kinase inhibitors.
Previously we reported that tyrosine kinase inhibitors (TKI) produced a reduction in uPA expression in prostatic cancer cells, and that TKI-treated cells were less invasive compared to untreated cells. Nevertheless, no change in cell migration was observed when TKI-treated cells were supplied with external uPA, thus indicating more complex mechanisms leading to decreased cell invasion. uPAR expression was measured with an enzyme-linked immunosorbent assay (ELISA) in PC-3 and DU-145 prostate carcinoma cells treated with the two TKI genistein and AG-1478. uPAR mRNA levels were measured with real-time reverse transcriptase-polymerase chain reaction (RT-PCR). uPAR immunocytochemistry was used to examine the receptor distribution in cells grown on a reconstituted basal lamina. Immunocytochemistry showed an intense uPAR immunostaining in invading cells, particularly in the leading edge membrane. Treatment with genistein and AG-1478 led to a decreased expression of uPAR in DU-145, but not in PC-3. Furthermore, a reduction of uPAR mRNA was found in TKI-treated DU-145 cells, while PC-3 was not affected. Our results indicate a possible role of TKI as cancer suppressors by acting as a regulator of uPAR expression.
Skogseth
Haakon
H
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Larsson
Erik
E
Halgunset
Jostein
J
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D020032:Tyrphostins / Q000494:pharmacology*
C524898:PLAUR protein, human; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D020032:Tyrphostins; C101044:RTKI cpd; D019833:Genistein; D011505:Protein-Tyrosine Kinases