title: The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21(BAX) expression.
abstract: Radiation is the primary modality of therapy for all commonly occurring malignant brain tumors, including medulloblastoma and glioblastoma. These two brain tumors, however, have a distinctly different response to radiation therapy. Medulloblastoma is very sensitive to radiation therapy, whereas glioblastoma is highly resistant, and the long-term survival of medulloblastoma patients exceeds 50%, while there are few long-term survivors among glioblastoma patients. p53-mediated apoptosis is thought to be an important mechanism mediating the cytotoxic response of tumors to radiotherapy. In this study, we compared the response to radiation of five cell lines that have wild-type p53: three derived from glioblastoma and two derived from medulloblastoma. We found that the medulloblastoma-derived cell lines underwent extensive radiation-induced apoptotic cell death, while those from glioblastomas did not exhibit significant radiation-induced apoptosis. p53-mediated induction of p21(BAX) is thought to be a key component of the pathway mediating apoptosis after the exposure of cells to cytotoxins, and the expression of mRNA encoding p21(BAX) was correlated with these cell lines undergoing radiation-induced apoptosis. The failure of p53 to induce p21(BAX) expression in glioblastoma-derived cell lines is likely to be of biologic significance, since inhibition of p21(BAX) induction in medulloblastoma resulted in a loss of radiation-induced apoptosis, while forced expression of p21(BAX) in glioblastoma was sufficient to induce apoptosis. The failure of p53 to induce p21(BAX) in glioblastoma-derived cell lines suggests a distinct mechanism of radioresistance and may represent a critical factor in determining therapeutic responsiveness to radiation in glioblastomas.
authors.affiliation: Preuss Laboratory for Molecular Neurooncology, Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Shu
authors.forename: M M
authors.initials: MM
authors.lastname: Kim
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Furman
authors.forename: C M
authors.initials: CM
authors.lastname: Julin
authors.forename: M A
authors.initials: MA
authors.lastname: Israel
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D001932:Brain Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004791:Enzyme Inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D016158:Genes, p53; D005909:Glioblastoma; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein