Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase

The type 1 insulin-like growth factor receptor (IGF1R) is required for grow th, tumorigenicity and protection from apoptosis, IGF1R overexpression is a ssociated with radioresistance in breast cancer. We used antisense (AS) RNA to downregulate IGF1R expression in mouse melanoma cells. Cells expressing AS-IGF1R transcripts were more radiosensitive in vitro and in vivo than co ntrols. Also they showed reduced radiation-induced p53 accumulation and p53 serine 18 phosphorylation, and radioresistant DNA synthesis. These changes were reminiscent of the cellular phenotype of the human genetic disorder a taxia-telangiectasia (A-T), caused by mutations in the A TM gene. Cellular Atm protein levels mere lower in AS-IGF1R-transfected cells than in control cells, although there was no difference in Atm expression at,the transcrip tional level. AS-IGF1R cells had detectable basal Atm kinase activity, but failed to induce kinase activity after irradiation. This suggests that IGF1 R signalling can modulate the function of Atm, and supports the concept of targeted IGF1R downregulation as a potential treatment for malignant melano ma and other radioresistant tumours.