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Aberrant expression of proteinase-activated receptor 4 promotes colon cancer cell proliferation through a persistent

Valérie Gratio1, Francine Walker, Thérèse Lehy

  • 1INSERM U773, Faculté de Médecine Xavier Bichat 75018 Paris, France.

International Journal of Cancer
|December 6, 2008
PubMed

Insights

The thrombin receptor PAR4 is expressed in human colon cancer cells, promoting cell growth. Inhibiting PAR4 signaling, particularly ErbB-2 and ERK pathways, could be a therapeutic strategy for colon tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Thrombin plays a role in cancer development.
  • Protease-activated receptor 4 (PAR4) is a recently discovered thrombin receptor.

Purpose of the Study:

  • To investigate the expression and function of PAR4 in human colon cancer.
  • To elucidate the signaling pathways involved in PAR4-mediated colon cancer cell proliferation.

Main Methods:

  • PAR4 mRNA expression analysis in colon cancer cell lines and normal colon epithelial cells.
  • Immunostaining of PAR4 in colon tumors and normal mucosa.
  • Functional assays measuring intracellular calcium and cell proliferation upon PAR4 activation.
  • Western blot analysis to assess signaling pathway activation (ERK1/2, ErbB-2).
  • Pharmacological inhibition of signaling pathways (ErbB, Src).

Main Results:

  • PAR4 mRNA and protein were detected in human colon cancer cell lines and tumors, but not in normal colon tissues.
  • PAR4 activation by its specific agonist AP4 stimulated intracellular calcium increase and dose-dependent mitogenic response in colon cancer cells.
  • PAR4 activation led to sustained extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation, involving epidermal growth factor receptor B-2 (ErbB-2) transactivation.
  • Inhibition of ErbB-2 and Src kinase reversed PAR4-induced ERK1/2 phosphorylation and cell proliferation.

Conclusions:

  • PAR4 is aberrantly expressed in human colon cancer and promotes tumor cell proliferation.
  • PAR4 signaling activates the ERK1/2 pathway through ErbB-2 transactivation, highlighting a critical role for Src kinase.
  • PAR4 represents a potential therapeutic target for colon cancer treatment.

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