Abstract
Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the signaling pathways downstream of PAR2 activation that lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events upon activation of PAR2 by the serine protease trypsin or the specific PAR2-activating peptide (AP2): (i) a matrix metalloproteinase-dependent release of transforming growth factor (TGF)-alpha, as demonstrated with TGF-alpha-blocking antibodies and measurement of TGF-alpha in culture medium; (ii) TGF-alpha-mediated activation of epidermal growth factor receptor (EGF-R) and subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent cell proliferation. The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-alpha-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R. These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation.
Highlights
Several lines of evidence suggest that tumor-derived ning domain G protein-coupled receptors comprising four retrypsin contributes to the growth and invasion of cancer cells
We investigated whether epidermal growth factor receptor (EGF-R) transactivation upon activation of PARs is mediated by release of transforming growth factor (TGF)-␣, the most abundant member of the EGF-R family ligands found in normal colon and colon carcinomas [18]
We recently showed that trypsin, acting at protease-activated receptor protease-activated receptor 2 (PAR2), is a potent growth factor for human colon cancer cells [14]
Summary
Several lines of evidence suggest that tumor-derived ning domain G protein-coupled receptors comprising four retrypsin contributes to the growth and invasion of cancer cells. The activation of PARs by these synthetic peptides APs is independent of receptor proteolysis [1, 2, 4] The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-␣-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation. The cellular pathways that transmit the proliferative signal induced by activation of PAR2 to the nu-
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