trp-lys-tyr-met-val-met and Lung-Neoplasms

Cross talk between unrelated cell surface receptors, such as G-protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTK), is a crucial signaling mechanism to expand the cellular communication network. We investigated the ability of the GPCR formyl peptide receptor-like 1 (FPRL1) to transactivate the RTK epidermal growth factor receptor (EGFR) in CaLu-6 cells. We observed that stimulation with WKYMVm, an FPRL1 agonist isolated by screening synthetic peptide libraries, induces EGFR tyrosine phosphorylation, p47(phox) phosphorylation, NADPH-oxidase-dependent superoxide generation, and c-Src kinase activity. As a result of EGFR transactivation, phosphotyrosine residues provide docking sites for recruitment and triggering of the STAT3 pathway. WKYMVm-induced EGFR transactivation is prevented by the FPRL1-selective antagonist WRWWWW, by pertussis toxin (PTX), and by the c-Src inhibitor PP2. The critical role of NADPH-oxidase-dependent superoxide generation in this cross-talk mechanism is corroborated by the finding that apocynin or a siRNA against p22(phox) prevents EGFR transactivation and c-Src kinase activity. In addition, WKYMVm promotes CaLu-6 cell growth, which is prevented by PTX and by WRWWWW. These results highlight the role of FPRL1 as a potential target of new drugs and suggest that targeting both FPRL1 and EGFR may yield superior therapeutic effects compared with targeting either receptor separately.

Topics: Cell Growth Processes; Cell Line, Tumor; CSK Tyrosine-Protein Kinase; ErbB Receptors; Humans; Lung Neoplasms; Molecular Targeted Therapy; NADPH Oxidases; Oligopeptides; Phosphorylation; Protein-Tyrosine Kinases; Pyrimidines; Reactive Oxygen Species; Receptor Cross-Talk; Receptors, Formyl Peptide; Receptors, Lipoxin; RNA, Small Interfering; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor; Transcriptional Activation