Inhibition of DNA repair by a herpes simplex virus vector enhances the radiosensitivity of human glioblastoma cells.
Expression of the herpes simplex virus (HSV) protein, ICP0, from the viral genome, rendered two radioresistant human glioblastoma multiforme cell lines more sensitive to the effects of ionizing radiation. Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic survival assays, U87-MG and T98 cell survival was more greatly decreased as a function of ionizing radiation dose when ICP0 was preexpressed in cells compared with when ICP0 was not expressed. Consistent with previous results, we found that the catalytic subunit of DNA-dependent protein kinase was degraded as a function of ICP0 in both cell types. This most likely resulted in the inhibition of DNA repair as inferred by the persistence of gammaH2AX foci or DNA double-strand breaks. Enhanced apoptosis was also found to occur following irradiation of U87-MG cells preinfected with the ICP0-producing HSV-1 mutant, d106. Our results suggest that expression of ICP0 in human glioblastoma multiforme cells inhibits the repair of DNA double-strand breaks after ionizing radiation treatment, decreasing the survival of these cells in part by induction of apoptosis.
Hadjipanayis
Costas G
CG
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
DeLuca
Neal A
NA
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D048708:Cell Growth Processes / Q000502:physiology; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000532:radiotherapy* / Q000821:virology; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000532:radiotherapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases