Low dose of wortmannin reduces radiosensitivity of human glioblastoma cells through the p53 pathway.
Wortmannin is an inhibitor of PI3-kinase and acts on cultured cells at dosages below 1 microM. Wortmannin also inhibits the gene products of the PI3-kinase family such as ATM or DNA-PK at dosages above 10 microM in cultured cells. There are many reports on the enhancement of radiosensitivity by a high dose of wortmannin inhibiting the proteins of the PI3-kinase family. However, there have been no reports on the effect on radiosensitivity of low doses of wortmannin inhibiting PI3-kinase. We found that low doses of wortmannin reduced the radiosensitivity of human A172 glioblastoma cells. This effect was shown only in wild-type p53 cells, but was not shown in mutant p53 cells such as T98G or A172/248W carrying a dominant point-mutated p53 gene. This result indicates that the PI3-kinase, or another wortmannin-sensitive enzyme, may affect the signal transduction of p53. We examined the response of the p53 pathway by X-ray irradiation. A low dose of wortmannin did not affect the accumulation of p53 and the phosphorylation of p53 at ser-15, but reduced the induction of WAF1 and enhanced the induction of GADD45.
Okaichi
Kumio
K
Department of Radiation Biophysics, Radiation Effect Research Unit, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Sakamoto, Nagasaki 852-8523, Japan. okaichi@net.nagasaki-u.ac.jp
Suzuki
Keiji
K
Morita
Naoko
N
Ikeda
Megumi
M
Takahashi
Haruki
H
Matsuda
Naoki
N
Watanabe
Masami
M
Okumura
Yutaka
Y
D000730:Androstadienes / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000077191:Wortmannin; D014965:X-Rays / Q000009:adverse effects
D000730:Androstadienes; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D000077191:Wortmannin