Wortmannin sensitizes human glioblastoma cell lines carrying mutant and wild type TP53 gene to radiation.
The purpose of this paper is to investigate the effect of wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), on TP53 (formerly known as p53) signal transduction initiated by ionizing radiation and radiosensitization in isogenic derivatives of human glioblastoma cells differing in TP53 status. Wortmannin inhibited the accumulation of TP53 and CDKN1A (formerly known as WAF1) after 6 Gy irradiation in A-172/neo cells bearing wild-type TP53. In A-172/Trp248 cells carrying mutant TP53, X-rays induced no significant accumulation of TP53 and slight increase of CDKN1A. There were, consequently, little differences in the expression of TP53 and CDKN1A between A-172/Trp248 cells exposed to 6 Gy alone and wortmannin plus 6 Gy. However, wortmannin sensitized both A-172/neo and A-172/Trp248 cells to radiation. These studies indicate that wortmannin inhibits TP53 upregulation, but this suppression does not account for the radiosensitization by this drug. These results indicate that inhibitors of PI3K-related kinases may present a new class of radiosensitizers, regardless of the TP53 status of tumor cells.
Kubota
N
N
Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Inashiki-gun, 300-0394, Ibaraki, Japan. kubota@ipu.ac.jp
Okada
S
S
Inada
T
T
Ohnishi
K
K
Ohnishi
T
T
D000730:Androstadienes / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D016158:Genes, p53 / Q000235:genetics*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D000077191:Wortmannin; D014965:X-Rays
D000730:Androstadienes; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D000077191:Wortmannin