Abstract
Insulin-like growth factor I receptor (IGF-IR) plays a pivotal role in cell growth, transformation, and cell survival. We found that cellular radioresistance is obtained when human wild-type IGF-IR is expressed in IGF-IR-knockout mouse embryo fibroblasts (R-). Mutational analysis revealed that the tyrosine at residue 950 (Y950) of IGF-IR, as well as the C-terminal domain, are required for radioresistance and that both domains must be mutated to abrogate the phenotype. Furthermore, the contribution of downstream pathways was analyzed by combining the use of wild-type or Y950 and C-terminal mutants with specific inhibitors of phosphatidylinositol 3-kinase (PI3-K) or mitogen-activated protein extracellular signal-regulated kinase (ERK) kinase (MEK). Radioresistance could be induced by IGF-IR as long as the ability of the receptor to stimulate the MEK/ERK pathway was retained. This was confirmed by the expression of constitutively active MEK in R- cells. The ability to stimulate the PI3-K pathway alone was not sufficient, but PI3-K activation coupled with MEK/ERK pathway-independent signals from the C-terminus was able to induce radioresistance. Collectively, these results indicate that the IGF-IR-mediated radioresistant signaling mechanism progresses through redundant downstream pathways. The redundancy of the survival signals related to the development of cellular radioresistance revealed by this study may have clinical implications regarding the use of molecular targeting in radiotherapy.
