1. ¹OncoRay – Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstrasse, Dresden, Germany
2. ²Bundeswehr Institute of Radiobiology, Neuherbergstrasse, Munich, Germany
3. ³Department of Radiation Oncology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Strasse, Munich, Germany
4. ⁴Department of Molecular Medicine, Max-Planck Institute for Biochemistry, Am Klopferspitz, Martinsried, Germany

Correspondence: Dr N Cordes, OncoRay – Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74/PF 86, 01307 Dresden, Germany. E-mail: Nils.Cordes@mailbox.tu-dresden.de

Received 4 July 2005; Revised 19 August 2005; Accepted 31 August 2005; Published online 10 October 2005.

Abstract

Integrin-mediated adhesion to extracellular matrix proteins confers resistance to radiation- or drug-induced genotoxic injury. To analyse the underlying mechanisms specific for 1-integrins, wild-type 1A-integrin-expressing GD251A cells were compared to GD251B cells, which express signaling-incompetent 1B variants. Cells grown on fibronectin, collagen-III, 1-integrin-IgG or poly-l-lysine were exposed to 0–6 Gy X-rays in presence or depletion of growth factors and phosphatidylinositol-3 kinase (PI3K) inhibitors (LY294002, wortmannin). In order to test the relevance of these findings in tumor cells, human A-172 glioma cells were examined under the same conditions after siRNA-mediated silencing of 1-integrins. We found that 1A-integrin-mediated adhesion to fibronectin, collagen-III or 1-IgG was essential for cell survival after radiation-induced genotoxic injury. Mediated by PI3K, pro-survival 1A-integrin/Akt signaling was critically involved in this process. Additionally, the 1-integrin downstream targets p130Cas and paxillin-impaired survival-regulating PI3K-dependent JNK. In A-172 glioma cells, 1-integrin knockdown and PI3K inhibition confirmed the central role of 1-integrins in Akt- and p130Cas/paxillin-mediated prosurvival signaling. These findings suggest 1-integrins as critical regulators of cell survival after radiation-induced genotoxic injury. Elucidation of the molecular circuitry of prosurvival 1-integrin-mediated signaling in tumor cells may promote the development of innovative molecular-targeted therapeutic antitumor strategies.