Linked Life Data

15010475

Source:http://linkedlifedata.com/resource/pubmed/id/15010475

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
2004-5-10
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
14
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
20927-34
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15010475-Cell Division, pubmed-meshheading:15010475-Cell Line, Tumor, pubmed-meshheading:15010475-Colonic Neoplasms, pubmed-meshheading:15010475-Humans, pubmed-meshheading:15010475-Kinetics, pubmed-meshheading:15010475-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:15010475-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:15010475-Mitogen-Activated Protein Kinases, pubmed-meshheading:15010475-Phosphorylation, pubmed-meshheading:15010475-Protein Tyrosine Phosphatases, pubmed-meshheading:15010475-Receptor, Epidermal Growth Factor, pubmed-meshheading:15010475-Receptor, PAR-2, pubmed-meshheading:15010475-Receptor Protein-Tyrosine Kinases, pubmed-meshheading:15010475-Transcriptional Activation, pubmed-meshheading:15010475-Trypsin, pubmed-meshheading:15010475-Tyrphostins
pubmed:year
2004
pubmed:articleTitle
Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation.
pubmed:affiliation
Neuroendocrinologie et Biologie Cellulaire Digestives, INSERM U410, Faculté de Médecine Xavier Bichat, 75018 Paris, France. darmoul@bichat.inserm.fr
pubmed:publicationType
Journal Article