Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation |
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| Authors: | Caruso Roberta Pallone Francesco Fina Daniele Gioia Valentina Peluso Ilaria Caprioli Flavio Stolfi Carmine Perfetti Alessandra Spagnoli Luigi Giusto Palmieri Giampiero Macdonald Thomas T Monteleone Giovanni |
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| 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. |
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| 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. |
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