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 growth, tumorigenicity and protection from apoptosis. IGF1R overexpression is associated 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 controls. 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 ataxia-telangiectasia (A-T), caused by mutations in the ATM gene. Cellular Atm protein levels were lower in AS-IGF1R-transfected cells than in control cells, although there was no difference in Atm expression at the transcriptional level. AS-IGF1R cells had detectable basal Atm kinase activity, but failed to induce kinase activity after irradiation. This suggests that IGF1R signalling can modulate the function of Atm, and supports the concept of targeted IGF1R downregulation as a potential treatment for malignant melanoma and other radioresistant tumours.
Macaulay
V M
VM
IGF Group, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, Oxford, OX3 9DS, UK. macaulay@icrf.icnet.uk
Salisbury
A J
AJ
Bohula
E A
EA
Playford
M P
MP
Smorodinsky
N I
NI
Shiloh
Y
Y
D000818:Animals; D017209:Apoptosis; D001260:Ataxia Telangiectasia / Q000473:pathology; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008546:Melanoma, Experimental / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011836:Radiation Tolerance / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000528:radiation effects / Q000637:transplantation
D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D017526:Receptor, IGF Type 1