title: β₁Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy.
abstract: Integrin signaling critically contributes to the progression, growth, and therapy resistance of malignant tumors. Here, we show that targeting of β₁ integrins with inhibitory antibodies enhances the sensitivity to ionizing radiation and delays the growth of human head and neck squamous cell carcinoma cell lines in 3D cell culture and in xenografted mice. Mechanistically, dephosphorylation of focal adhesion kinase (FAK) upon inhibition of β₁ integrin resulted in dissociation of a FAK/cortactin protein complex. This, in turn, downregulated JNK signaling and induced cell rounding, leading to radiosensitization. Thus, these findings suggest that robust and selective pharmacological targeting of β₁ integrins may provide therapeutic benefit to overcome tumor cell resistance to radiotherapy.
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Eke
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Deuse
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hehlgans
authors.forename: Kristin
authors.initials: K
authors.lastname: Gurtner
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.forename: Anna
authors.initials: A
authors.lastname: Shevchenko
authors.forename: Veit
authors.initials: V
authors.lastname: Sandfort
authors.forename: Nils
authors.initials: N
authors.lastname: Cordes
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051356:Cortactin / Q000737:chemistry / Q000502:physiology*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000737:chemistry / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D019012:Integrin beta1 / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000528:radiation effects
chemical_list: D000911:Antibodies, Monoclonal; C495868:CTTN protein, human; D051356:Cortactin; D019012:Integrin beta1; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D048056:Mitogen-Activated Protein Kinase 9; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048055:Mitogen-Activated Protein Kinase 8