Dehydroepiandrosterone augments sensitivity to gamma-ray irradiation in human H4 neuroglioma cells through down-regulation of Akt signaling.
Dehydroepiandrosterone (DHEA) modulates sensitivity to radiation-induced injury in human neuroglioma cells (H4) through effects on Akt signalling by glutathione (GSH)-dependent redox regulation. Previous treatment of H4 cells with DHEA for 18 h reduced the gamma-ray-induced phosphorylation of Akt, activated p21(waf1) synthesis and up-regulated phosphorylation of Rb independent of p53. These reactions were followed by a decrease in cell number and an increase in apoptosis and G(2)/M checkpoint arrest. The suppression of phosphorylation of Akt by DHEA was due to regulation of the dephosphorylation by protein phosphatase 2A (PP2A). DHEA up-regulated the expression of gamma-glutamylcysteine synthetase, a rate-limiting enzyme of glutathione (GSH) synthesis, and the levels of GSH to maintain PP2A activity. The results suggested that DHEA increases the sensitivity of cells to gamma-ray irradiation by inducing apoptosis and cell cycle arrest through GSH-dependent regulation of the reduced form of PP2A to down-regulate the Akt signalling pathway.
Hirao
Tomohito
T
Department of Biochemistry and Molecular Biology in Disease, Nagasaki University Graduate School of Biomedical Sciences, 1-2-14 Sakamoto, Nagasaki 852-8523, Japan.
Urata
Yoshishige
Y
Kageyama
Kan
K
Ikezaki
Midori
M
Kawakatsu
Miho
M
Matsuse
Michiko
M
Matsuo
Takayuki
T
Akishita
Masahiro
M
Nagata
Izumi
I
Kondo
Takahito
T
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D005720:Gamma Rays; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D005722:gamma-Glutamylcyclotransferase / Q000378:metabolism
D003687:Dehydroepiandrosterone; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D005722:gamma-Glutamylcyclotransferase; D005978:Glutathione