Abstract
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Radiotherapy & Oncology |
| Vol/bind | 76 |
| Udgave nummer | 2 |
| Sider (fra-til) | 129-34 |
| Antal sider | 5 |
| ISSN | 0167-8140 |
| DOI | |
| Status | Udgivet - 2005 |
Bibliografisk note
Keywords: 1-Phosphatidylinositol 3-Kinase; Animals; Antigens, CD29; Cell Line; Cell Survival; Colony-Forming Units Assay; Crk-Associated Substrate Protein; Fibroblasts; Focal Adhesion Protein-Tyrosine Kinases; Growth Substances; JNK Mitogen-Activated Protein Kinases; Paxillin; Proto-Oncogene Proteins c-akt; Radiation Tolerance; Signal TransductionAdgang til dokumentet
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I: Radiotherapy & Oncology, Bind 76, Nr. 2, 2005, s. 129-34.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
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TY - JOUR
T1 - Interactions of the integrin subunit beta1A with protein kinase B/Akt, p130Cas and paxillin contribute to regulation of radiation survival.
AU - Seidler, Julia
AU - Durzok, Rita
AU - Brakebusch, Cord
AU - Cordes, Nils
N1 - Keywords: 1-Phosphatidylinositol 3-Kinase; Animals; Antigens, CD29; Cell Line; Cell Survival; Colony-Forming Units Assay; Crk-Associated Substrate Protein; Fibroblasts; Focal Adhesion Protein-Tyrosine Kinases; Growth Substances; JNK Mitogen-Activated Protein Kinases; Paxillin; Proto-Oncogene Proteins c-akt; Radiation Tolerance; Signal Transduction
PY - 2005
Y1 - 2005
N2 - BACKGROUND AND PURPOSE: Cell adhesion-mediated radioresistance is a common phenomenon particularly relevant in tumor cells, which might hamper anticancer therapies. To analyze the role of adhesion-mediating beta1-integrins, stably transfected functional beta1A-integrin-expressing GD25beta1A and GD25beta1B cells, which express mutant beta1B-integrins, were compared in terms of radiation survival and beta1-integrin signaling. MATERIALS AND METHODS: Cells grown on fibronectin, collagen-III, laminin, vitronectin, anti-beta1-integrin-IgG (beta1-IgG) or poly-l-lysine were irradiated with 0-6Gy in presence or absence of growth factors or inhibitors for phosphatidylinositol-3 kinase (PI3K), i.e. Ly294002 and wortmannin. In addition to colony formation, protein kinase B/Akt (PKB/Akt) kinase activity, focal adhesion kinase (FAK), p130Cas, paxillin and c-Jun N2-terminal kinase (JNK) expression and phosphorylation were analyzed by Western blot technique. RESULTS: Adhesion of GD25beta1A cells to extracellular matrix proteins or beta1-IgG resulted in growth factor-independent radiation survival. In contrast, serum starved GD25beta1B cells showed a significant (P<0.01) reduction in radiation survival on all substrates. PI3K inhibition moderately or strongly radiosensitized GD25beta1A or GD25beta1B cells, respectively. The pro-survival effects detected in serum starved GD25beta1A cells were due to direct, PI3K-mediated stimulation of PKB/Akt activity by beta1-integrins and induced p130Cas and paxillin phosphorylation. Phosphorylated p130Cas and paxillin subsequently prevented activation of cell death-regulating JNK. CONCLUSIONS: The data show that beta1-integrin-mediated signaling through the cytoplasmic integrin domains is critical for efficient pro-survival regulation after irradiation. Profound knowledge of the underlying mechanisms of integrin-mediated cellular radioresistance could foster the design of new molecular-targeted anticancer therapies.
AB - BACKGROUND AND PURPOSE: Cell adhesion-mediated radioresistance is a common phenomenon particularly relevant in tumor cells, which might hamper anticancer therapies. To analyze the role of adhesion-mediating beta1-integrins, stably transfected functional beta1A-integrin-expressing GD25beta1A and GD25beta1B cells, which express mutant beta1B-integrins, were compared in terms of radiation survival and beta1-integrin signaling. MATERIALS AND METHODS: Cells grown on fibronectin, collagen-III, laminin, vitronectin, anti-beta1-integrin-IgG (beta1-IgG) or poly-l-lysine were irradiated with 0-6Gy in presence or absence of growth factors or inhibitors for phosphatidylinositol-3 kinase (PI3K), i.e. Ly294002 and wortmannin. In addition to colony formation, protein kinase B/Akt (PKB/Akt) kinase activity, focal adhesion kinase (FAK), p130Cas, paxillin and c-Jun N2-terminal kinase (JNK) expression and phosphorylation were analyzed by Western blot technique. RESULTS: Adhesion of GD25beta1A cells to extracellular matrix proteins or beta1-IgG resulted in growth factor-independent radiation survival. In contrast, serum starved GD25beta1B cells showed a significant (P<0.01) reduction in radiation survival on all substrates. PI3K inhibition moderately or strongly radiosensitized GD25beta1A or GD25beta1B cells, respectively. The pro-survival effects detected in serum starved GD25beta1A cells were due to direct, PI3K-mediated stimulation of PKB/Akt activity by beta1-integrins and induced p130Cas and paxillin phosphorylation. Phosphorylated p130Cas and paxillin subsequently prevented activation of cell death-regulating JNK. CONCLUSIONS: The data show that beta1-integrin-mediated signaling through the cytoplasmic integrin domains is critical for efficient pro-survival regulation after irradiation. Profound knowledge of the underlying mechanisms of integrin-mediated cellular radioresistance could foster the design of new molecular-targeted anticancer therapies.
U2 - 10.1016/j.radonc.2005.06.018
DO - 10.1016/j.radonc.2005.06.018
M3 - Journal article
C2 - 16024122
SN - 0167-8140
VL - 76
SP - 129
EP - 134
JO - Radiotherapy & Oncology
JF - Radiotherapy & Oncology
IS - 2
ER -