Methylation of the ATM promoter in glioma cells alters ionizing radiation sensitivity.
Glioblastomas are among the malignancies most resistant to radiation therapy. In contrast, cells lacking the ATM protein are highly sensitive to ionizing radiation. The relationship between ATM protein expression and radiosensitivity in 3 glioma cell lines was examined. T98G cells exhibited normal levels of ATM protein, whereas U118 and U87 cells had significantly lower levels of ATM and increased (>2-fold) sensitivity to ionizing radiation compared to T98G cells. The ATM promoter was methylated in U87 cells. Demethylation by azacytidine treatment increased ATM protein levels in the U87 cells and decreased their radiosensitivity. In contrast, the ATM promoter in U118 cells was not methylated. Further, expression of exogenous ATM did not significantly alter the radiosensitivity of U118 cells. ATM expression is therefore heterogeneous in the glioma cells examined. In conclusion, methylation of the ATM promoter may account for the variable radiosensitivity and heterogeneous ATM expression in a fraction of glioma cells.
Roy
Kanaklata
K
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
Wang
Lilin
L
Makrigiorgos
G Mike
GM
Price
Brendan D
BD
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005910:Glioma / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D008745:Methylation / Q000528:radiation effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases