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 β₁ integrins promote resistance to radiation. For this purpose, we conditionally ablated β₁ integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β₁ to promote resistance to radiation was also analyzed by using an inhibitory antibody to β₁, AIIB2, in a xenograft model. The role of β₁ integrins and of a β₁ downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β₁ integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β₁ 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 β₁ on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between β₁ integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β₁ integrin levels. We report that IGF-IR regulates the expression of β₁ integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β₁ integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. J. Cell. Physiol. 228: 1601-1609, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]