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