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  • Original Article
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β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

Oncogene volume 25, pages 1378–1390 (2006)Cite this article

Abstract

Integrin-mediated adhesion to extracellular matrix proteins confers resistance to radiation- or drug-induced genotoxic injury. To analyse the underlying mechanisms specific for β1-integrins, wild-type β1A-integrin-expressing GD25β1A cells were compared to GD25β1B cells, which express signaling-incompetent β1B variants. Cells grown on fibronectin, collagen-III, β1-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 β1-integrins. We found that β1A-integrin-mediated adhesion to fibronectin, collagen-III or β1-IgG was essential for cell survival after radiation-induced genotoxic injury. Mediated by PI3K, pro-survival β1A-integrin/Akt signaling was critically involved in this process. Additionally, the β1-integrin downstream targets p130Cas and paxillin-impaired survival-regulating PI3K-dependent JNK. In A-172 glioma cells, β1-integrin knockdown and PI3K inhibition confirmed the central role of β1-integrins in Akt- and p130Cas/paxillin-mediated prosurvival signaling. These findings suggest β1-integrins as critical regulators of cell survival after radiation-induced genotoxic injury. Elucidation of the molecular circuitry of prosurvival β1-integrin-mediated signaling in tumor cells may promote the development of innovative molecular-targeted therapeutic antitumor strategies.

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Abbreviations

ECM:

extracellular matrix

FAK:

focal adhesion kinase

ILK:

integrin-linked kinase

p130Cas:

Crk-associated substrate

Akt:

protein kinase B/Akt

PI3K:

phosphatidylinositol-3 kinase

MAPK:

mitogen-activated protein kinase

JNK:

c-Jun N2-terminal kinase

FN:

fibronectin

ColIII:

collagen-III

β1-IgG:

anti-β1-integrin-IgG

PLL:

poly-l-lysine

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Acknowledgements

The authors thank Dr Fässler (Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried, Germany) and Dr Velling (Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Sweden) for kindly providing the cell lines. We also thank Ms Bärbel Reincke and Mr Ralph Hartmann for excellent technical assistance.

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Authors and Affiliations

  1. OncoRay – Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstrasse, Dresden, Germany

    N Cordes, J Seidler & R Durzok

  2. Bundeswehr Institute of Radiobiology, Neuherbergstrasse, Munich, Germany

    N Cordes

  3. Department of Radiation Oncology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Strasse, Munich, Germany

    H Geinitz

  4. Department of Molecular Medicine, Max-Planck Institute for Biochemistry, Am Klopferspitz, Martinsried, Germany

    C Brakebusch

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Correspondence to N Cordes.

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Cordes, N., Seidler, J., Durzok, R. et al. β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury. Oncogene 25, 1378–1390 (2006). https://doi.org/10.1038/sj.onc.1209164

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