beta1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase1

Abstract

This study was carried out to dissect the mechanism by which beta1 integrins promote resistance to radiation. For this purpose, we conditionally ablated beta1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of beta1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to beta1, AIIB2, in a xenograft model. The role of beta1 integrins and of a beta1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that beta1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, beta1 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 beta1 on resistance to radiation in vitro and in vivo. Finally, given the established cross-talk between beta1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate beta1 integrin levels. We report that IGF-IR regulates the expression of beta1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that beta1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation.