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Urokinase plasminogen activator receptor (uPAR) expression is reduced by tyrosine kinase inhibitors

Haakon Skogseth1, Erik Larsson, Jostein Halgunset

  • 1Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica
|May 13, 2006
PubMed

Insights

Tyrosine kinase inhibitors (TKI) reduce prostate cancer cell invasion by regulating urokinase plasminogen activator receptor (uPAR) expression. This suggests TKIs may act as cancer suppressors by modulating uPAR.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tyrosine kinase inhibitors (TKI) previously showed reduced uPA expression and invasiveness in prostate cancer cells.
  • Complex mechanisms beyond external urokinase plasminogen activator (uPA) influence TKI-mediated decreases in cell invasion.

Purpose of the Study:

  • To investigate the effect of genistein and AG-1478 (TKIs) on urokinase plasminogen activator receptor (uPAR) expression and distribution in prostate carcinoma cells (PC-3 and DU-145).
  • To determine if TKIs regulate uPAR as a mechanism for their anti-invasive effects.

Main Methods:

  • Enzyme-linked immunosorbent assay (ELISA) to quantify uPAR protein expression.
  • Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to measure uPAR mRNA levels.
  • Immunocytochemistry to visualize uPAR distribution in cells on a reconstituted basal lamina.

Main Results:

  • Genistein and AG-1478 decreased uPAR expression in DU-145 cells, but not PC-3 cells.
  • A reduction in uPAR mRNA was observed in TKI-treated DU-145 cells, with no significant effect on PC-3 cells.
  • Immunocytochemistry revealed intense uPAR staining at the leading edge of invading cells.

Conclusions:

  • TKIs, specifically genistein and AG-1478, can regulate uPAR expression in prostate cancer cells.
  • The differential effect of TKIs on uPAR expression in DU-145 versus PC-3 cells highlights cell-specific responses.
  • These findings suggest a potential role for TKIs as cancer suppressors through the regulation of uPAR.

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