Celecoxib increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation.

摘要: // Roberta Vene 1,2 , Francesca Tosetti 2 Simona Minghelli Alessandro Poggi Nicoletta Ferrari and Roberto Benelli 1 Immunology Lab, IRCCS AOU San Martino - IST, Genoa, Italy Molecular Oncology Angiogenesis Correspondence to: Benelli, email: Keywords : EGFR, celecoxib, colon, fibroblast Received October 01, 2014 Accepted March 11, 2015 Published 29, Abstract We previously demonstrated that non-toxic doses of Celecoxib induced the immediate phosphorylation Erk1-2 in colon tumor associated fibroblasts (TAFs), increasing their responsiveness to epidermal growth factor (EGF). have now identified two concomitant mechanisms explaining EGF-Celecoxib cooperation. found a 24-48h priming increased EGF receptor (EGFR) mRNA protein levels TAFs, promoting binding internalization. Celecoxib-primed TAFs showed reduced EGFR degradation after challenge. This delay corresponded deferred dissociation EEA1 from positive endosomes accumulation Rab7, pro Cathepsin-D SQSTM1/p62, suggesting shared bottleneck pathways late-endosomes/autophagosomes maturation. modulated target proteins similarly inhibitors endosome/lysosome acidification Bafilomycin-A1 NH 4 Cl. Cytoplasmic vesicles fractionation maturation late an content Rab7 lysosomes Celecoxib-treated TAFs. Our data indicate double mechanism mediating response treated with Celecoxib. While overexpression could be targeted using anti drugs, effects on endosome trafficking turnover represents more elusive should taken into account for any long-term therapy