β1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1

This study was carried out to dissect the mechanism by which 1 integrins promote resistance to radiation. For this purpose, we conditionally ablated 1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of 1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to 1, AIIB2, in a xenograft model. The role of 1 integrins and of a 1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that 1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, 1 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 1 on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between 1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate 1 integrin levels. We report that IGF-IR regulates the expression of 1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that 1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. J. Cell. Physiol. 228: 16011609, 2013. (c) 2013 Wiley Periodicals, Inc.