title: α integrin targeting for radiosensitization of three-dimensionally grown human head and neck squamous cell carcinoma cells.
abstract: Integrin cell adhesion molecules play a crucial role in tumor cell resistance to radio- and chemotherapy and are therefore considered attractive targets for cancer therapy. Here, we assessed the role of β1 integrin-interacting α integrin subunits in more physiological three-dimensional extracellular matrix grown head and neck squamous cell carcinoma (HNSCC) cell cultures for evaluating cytotoxic and radiosensitizing potential. α2, α3, α5 and α6 integrins, which are overexpressed in HNSCC according to Oncomine database analysis, were coprecipitated with β1 integrin. More potently than α2, α5 or α6 integrin inhibition, siRNA-based α3 integrin targeting resulted in reduced clonogenic cell survival, induced apoptosis and enhanced radiosensitivity. These events were associated with diminished phosphorylation of Akt, Cortactin and Paxillin. Cell line-dependently, simultaneous α3 and β1 integrin inhibition led to higher cytotoxicity and radiosensitization than α3 integrin blocking alone. Stable overexpression of wild-type and constitutively active forms of the integrin signaling mediator focal adhesion kinase (FAK) revealed FAK as a key determinant of α3 integrin depletion-mediated radiosensitization. Our findings show that α3 integrin is essentially involved in HNSCC cell radioresistance and critical for a modified cellular radiosensitivity along with β1 integrins.
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Steglich
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Vehlow
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Eke
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany; Institute of Radiooncology, Helmholtz-Zentrum Dresden - Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany; German Cancer Consortium (DKTK), Fetscherstr. 74, 01307 Dresden, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: nils.cordes@oncoray.de.
authors.forename: Nils
authors.initials: N
authors.lastname: Cordes
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects*; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics / Q000378:metabolism; D039422:Integrin alpha3 / Q000235:genetics / Q000378:metabolism*; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism; D039503:Integrin alpha6 / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects
chemical_list: D039421:Integrin alpha2; D039422:Integrin alpha3; D039482:Integrin alpha5; D039503:Integrin alpha6; D019012:Integrin beta1; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: FAK; Head and neck cancer; Radiosensitivity; α3 integrin; β1 integrin