beta1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury.

Abstract

Integrin-mediated adhesion to extracellular matrix proteins confers resistance to radiation- or drug-induced genotoxic injury. To analyse the underlying mechanisms specific for beta1-integrins, wild-type beta1A-integrin-expressing GD25beta1A cells were compared to GD25beta1B cells, which express signaling-incompetent beta1B variants. Cells grown on fibronectin, collagen-III, beta1-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 beta1-integrins. We found that beta1A-integrin-mediated adhesion to fibronectin, collagen-III or beta1-IgG was essential for cell survival after radiation-induced genotoxic injury. Mediated by PI3K, pro-survival beta1A-integrin/Akt signaling was critically involved in this process. Additionally, the beta1-integrin downstream targets p130Cas and paxillin-impaired survival-regulating PI3K-dependent JNK. In A-172 glioma cells, beta1-integrin knockdown and PI3K inhibition confirmed the central role of beta1-integrins in Akt- and p130Cas/paxillin-mediated prosurvival signaling. These findings suggest beta1-integrins as critical regulators of cell survival after radiation-induced genotoxic injury. Elucidation of the molecular circuitry of prosurvival beta1-integrin-mediated signaling in tumor cells may promote the development of innovative molecular-targeted therapeutic antitumor strategies.

• Authors: N Cordes, J Seidler, R Durzok, H Geinitz, C Brakebusch
• Journal: Oncogene (Oncogene) Vol. 25 Issue 9 Pg. 1378-90 (Mar 02 2006) ISSN: 0950-9232 [Print] England
• PMID: 16247454 (Publication Type: Journal Article)

Chemical References

• Extracellular Matrix Proteins
• Fibronectins
• Growth Substances
• Integrin beta1
• RNA, Small Interfering
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Brain Neoplasms (pathology)
• Cell Adhesion
• Cell Culture Techniques
• Cell Survival
• Extracellular Matrix Proteins
• Fibroblasts
• Fibronectins (metabolism)
• Glioma (pathology)
• Growth Substances
• Humans
• Integrin beta1 (physiology)
• Mice
• Proto-Oncogene Proteins c-akt (physiology)
• RNA, Small Interfering
• Radiation Injuries
• Signal Transduction
• Tumor Cells, Cultured
• X-Rays