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β 1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c‐Jun amino terminal kinase 1
Author(s) -
Goel Hira Lal,
Sayeed Aejaz,
Breen Michael,
Zarif Matthew J.,
Garlick David S.,
Leav Irwin,
Davis Roger J.,
FitzGerald Thomas J.,
Morrione Andrea,
Hsieh ChungCheng,
Liu Qin,
Dicker Adam P.,
Altieri Dario C.,
Languino Lucia R.
Publication year - 2013
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24323
Subject(s) - tramp , integrin , microbiology and biotechnology , in vivo , downregulation and upregulation , cancer research , ionizing radiation , biology , radioresistance , kinase , apoptosis , chemistry , receptor , prostate cancer , cell culture , cancer , biochemistry , irradiation , genetics , physics , gene , nuclear physics
This study was carried out to dissect the mechanism by which β 1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β 1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β 1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β 1 , AIIB2, in a xenograft model. The role of β 1 integrins and of a β 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 β 1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β 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 β 1 on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between β 1 integrins and type1 insulin‐like growth factor receptor (IGF‐IR), we analyzed the ability of IGF‐IR to modulate β 1 integrin levels. We report that IGF‐IR regulates the expression of β 1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β 1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. J. Cell. Physiol. 228: 1601–1609, 2013. © 2013 Wiley Periodicals, Inc.