RESUMO
This study was carried out to dissect the mechanism by which ß1 integrins promote resistance to radiation. For this purpose, we conditionally ablated ß1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of ß1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to ß1 , AIIB2, in a xenograft model. The role of ß1 integrins and of a ß1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that ß1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, ß1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of ß1 on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between ß1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate ß1 integrin levels. We report that IGF-IR regulates the expression of ß1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that ß1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation.
Assuntos
Integrina beta1/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Tolerância a Radiação/fisiologia , Animais , Apoptose/fisiologia , Apoptose/efeitos da radiação , Caspase 3/metabolismo , Linhagem Celular Tumoral , Humanos , Integrina beta1/genética , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Camundongos Transgênicos , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/genética , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transplante HeterólogoRESUMO
Cell adhesion receptors, referred to as integrins, are recognized as key regulators of cellular processes including growth and differentiation. Integrins communicate with growth factor receptors (GFRs) to control specific cellular responses to stimuli originating in the extracellular environment. In this article, we review the role of integrins as molecular switches that modulate GFR activation and specificity. We also examine the reciprocal modulation of integrin functions by GFRs and the mechanisms through which those actions are fine-tuned.