Ionizing radiation activates IGF-1R triggering a cytoprotective signaling by interfering with Ku-DNA binding and by modulating Ku86 expression via a p38 kinase-dependent mechanism.
Ionizing radiation exposure results in the activation of several tyrosine kinase receptors that participate in radiation-induced DNA damage response and radioresistance. We previously showed that insulin-like growth factor 1 receptor (IGF-1R) inhibition enhanced radiosensitivity of non-small-cell lung cancer (NSCLC) cells. In this paper, we demonstrate that in U1810 NSCLC cells gamma-radiation activates IGF-1R within 10 min, with a maximal activation effect 2 h post-irradiation. Impairment of IGF-1R tyrosine kinase activity enhances human lung cancer cells radiosensitivity by a mechanism that involves phosphatidylinositol 3-kinase (PI3-K) and p38 kinase. In an active form, IGF-1R binds and activates p38 kinase, promoting receptor signaling. Conversely, inhibition of IGF-1R phosphorylation results in IGF-1R/p38 complex disruption and p38 kinase inactivation. We have also demonstrated that in insulin-like growth factor-1-stimulated cells, Ku-DNA-binding activation is induced by ionizing radiation within 4 h, reaches a maximum level at 12 h and remains active up to 72 h. Blockade of IGF-1R activity or its downstream signaling through p38 kinase induces a decrease in radiation-mediated Ku-DNA-binding activation and downregulates the level of Ku86, without affecting Ku70 expression in the nucleus of U1810 cells. The IGF-1R signaling via PI3-K does not interfere with the p38 signaling, the Ku-DNA-binding activity or the level of Ku86. Our present study demonstrates for the first time that ionizing radiation activates IGF-1R. Inhibition of IGF-1R signaling via p38 kinase induces radiosensitivity by a novel mechanism involving nuclear Ku86.
Cosaceanu
D
D
Department of Oncology-Pathology, Cancer Center Karolinska and Radiumhemmet Karolinska Institute/Hospital, Stockholm, Sweden.
Budiu
R A
RA
Carapancea
M
M
Castro
J
J
Lewensohn
R
R
Dricu
A
A
D034961:Antigens, Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005720:Gamma Rays; D006801:Humans; D000072200:Ku Autoantigen; D011485:Protein Binding / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects*; D015398:Signal Transduction / Q000528:radiation effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen