Dehydroepiandrosterone augments sensitivity to γ-ray irradiation in human H4 neuroglioma cells through down-regulation of Akt signaling

• Published in: Free radical research 2008-11, Vol.42 (11-12), p.957-965
• Main Authors: Hirao, Tomohito, Urata, Yoshishige, Kageyama, Kan, Ikezaki, Midori, Kawakatsu, Miho, Matsuse, Michiko, Matsuo, Takayuki, Akishita, Masahiro, Nagata, Izumi, Kondo, Takahito
• Format: Article
• Language: English
• Subjects: Akt; Apoptosis - drug effects; Apoptosis - radiation effects; Cell Count; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Dehydroepiandrosterone; Dehydroepiandrosterone - pharmacology; Gamma Rays; gamma-Glutamylcyclotransferase - metabolism; glutathione; Glutathione - metabolism; Humans; Oxidation-Reduction; Protein Phosphatase 2 - metabolism; protein phosphatase 2A; Proto-Oncogene Proteins c-akt - metabolism; radiation; Radiation Tolerance; Signal Transduction - drug effects; Signal Transduction - radiation effects; Tumor Cells, Cultured; γ-glutamylcysteine synthetase
• ISSN: 1071-5762; 1029-2470
• DOI: 10.1080/10715760802566582

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 γ-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 γ-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 γ-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.