title: β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells.
abstract: Lung cancer is the leading cause of cancer death worldwide. The epidermal growth factor receptor (EGFR) represents the main target for non-small cell lung cancer (NSCLC) therapy, as its overexpression or constitutive activation contributes to malignancy and correlates with poor prognosis. Our previous work demonstrated that in epithelial cells β1 integrin is required for propagating EGFR signaling from the plasma membrane to the nucleus. In this study, we silenced β1 integrin in human NSCLC A549 cells. The β1 integrin-silenced cells show a defective activation of the EGFR signaling cascade, leading to decreased in vitro proliferation, enhanced sensitivity to cisplatin and Gefitinib, impaired migration and invasive behavior. Inhibitory effects on tumor growth and on the EGFR pathway were also observed in in vivo experiments. Moreover, β1 integrin silencing increases the amount of EGFR on the cell surface, suggesting that β1 integrin is required for efficient constitutive EGFR turnover at the cell membrane. Although the rate of EGF internalization and recycling is not affected in silenced cells, EGFR signaling is recovered only by expression of the Rab-coupling protein RCP, indicating that β1 integrin sustains the endocytic machinery required for EGFR signaling. Overall, these results show that β1 integrin is an essential regulator of EGFR signaling and tumorigenic properties of lung cancer cells, and that its silencing might represent an adjuvant approach to anti-EGFR therapy.
authors.affiliation: Molecular Biotechnology Center, University of Torino, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Morello
authors.forename: S
authors.initials: S
authors.lastname: Cabodi
authors.forename: S
authors.initials: S
authors.lastname: Sigismund
authors.forename: M P
authors.initials: MP
authors.lastname: Camacho-Leal
authors.forename: D
authors.initials: D
authors.lastname: Repetto
authors.forename: M
authors.initials: M
authors.lastname: Volante
authors.forename: M
authors.initials: M
authors.lastname: Papotti
authors.forename: E
authors.initials: E
authors.lastname: Turco
authors.forename: P
authors.initials: P
authors.lastname: Defilippi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D019012:Integrin beta1; D008565:Membrane Proteins; D011799:Quinazolines; C488966:RAB11FIP1 protein, human; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D000077156:Gefitinib