EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) ACTIVATION BY GASTRIN RELEASING PEPTIDE (GRP) IN HEAD AND NECK CANCER: MECHANISMS AND CLINICAL IMPLICATIONS

摘要: Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR). We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide (GRP/GRPR) autocrine pathway is activated early in HNSCC carcinogenesis. GRP can induce rapid phosphorylation EGFR as well p42/44 MAPK activation, part via extracellular release transforming alpha(TGF-alpha) matrix metalloproteinases (MMP). Src family kinases have been to be G-protein-coupled receptors (GPCRs) followed downstream activation. To further elucidate mechanism activation HNSCC, we investigated role kinases. Blockade using three different Src-specific tyrosine kinase inhibitors (A-419259, PP2 or PD0180970) decreased GRP-induced also failed dominant-negative c-Src transfected cells. Invasion assays demonstrated was required for proliferation invasion In addition TGF-alpha release, induced amphiregulin, but not EGF, secretion into culture medium, an effect blocked MMP inhibitor, Marimastat. amphiregulin stimulation inhibited blockade Further investigation showed TNF-alpha converting enzyme (TACE) underwent Src-dependent translocation plasma membrane complex with p85 subunit PI-3 kinase, where it regulated release. addition, identified PDK1 target directly phosphorylated TACE. Knockdown augmented anti-tumor effects inhibitor erlotinib. These findings implicate new suggest therapeutic strategies block may improve clinical response inhibitors.Combined targeting GRPR enhanced efficacy inhibiting cancer proliferation, promoting apoptosis. Overall, these show promises benefits combination therapy when pathways head cancer.