title: Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation.
abstract: Dysregulated epidermal growth factor receptor (EGFR) signaling is involved in gastric cancer (GC) cell growth. However, the mechanism that sustains EGFR signaling in GC remains unknown. Since protease-activated receptor-2 (PAR-2), a G protein-coupled receptor, has been shown to trans-activate EGFR in several cell types, we examined the role of PAR-2 in GC. We show here that in vitro activation of PAR-2 enhances the growth of two GC cell lines, AGS and MKN28. In both these cell lines, PAR-2 trans-activated EGFR and inhibition of EGFR tyrosine kinase activity by AG1478 or specific EGFR siRNA completely prevented PAR-2-driven proliferation. Antibody blockade of EGF-like ligands to EGFR did not modify EGFR signaling or cell growth induced by PAR-2 activation. In contrast, PAR-2 promoted Src activation and interaction of this kinase with EGFR. In support of this, inhibition of Src kinase activity by PP1 or siRNA blocked PAR-2-induced EGFR signaling cascade and cell growth. Finally, PAR-2 was detectable in both normal and GC specimens, but its expression was more pronounced in GC than controls and correlated with activated EGFR. These data show that PAR-2 is overexpressed in GC and suggest a role of PAR-2 in EGFR trans-activation and cell growth.
authors.affiliation: Department of Internal Medicine and the Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, University "Tor Vergata" of Rome, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Daniele
authors.initials: D
authors.lastname: Fina
authors.forename: Valentina
authors.initials: V
authors.lastname: Gioia
authors.forename: Ilaria
authors.initials: I
authors.lastname: Peluso
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Perfetti
authors.forename: Luigi Giusto
authors.initials: LG
authors.lastname: Spagnoli
authors.forename: Giampiero
authors.initials: G
authors.lastname: Palmieri
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Macdonald
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D044464:Receptor, PAR-2; D066246:ErbB Receptors; D019061:src-Family Kinases