Li., L., Steinauer, K. L., Dirks, A. J., Husbeck, B., Gibbs, I. and Knox, S. J. Radiation-Induced Cyclooxygenase 2 Up-Regulation is Dependent on Redox Status in Prostate Cancer Cells. Radiat. Res. 160, 617–621 (2003).

Cyclooxygenase 2 (COX2) is the inducible isozyme of COX, a key enzyme in arachidonate metabolism and the conversion of arachidonic acid (AA) to prostaglandins (PGs) and other eicosanoids. Previous studies have demonstrated that the COX2 protein is up-regulated in prostate cancer cells after irradiation and that this results in elevated levels of PGE₂. In the present study, we further investigated whether radiation-induced COX2 up-regulation is dependent on the redox status of cells from the prostate cancer cell line PC-3. l-Buthionine sulfoximine (BSO), which inhibits gamma glutamyl cysteine synthetase (γGCS), and the antioxidants α-lipoic acid and N-acetyl-l-cysteine (NAC) were used to modulate the cellular redox status. BSO decreased the cellular GSH level and increased cellular reactive oxygen species (ROS) in PC-3 cells, whereas α-lipoic acid and NAC increased the GSH level and decreased cellular ROS. Both radiation and the oxidant H₂O₂ had similar effects on COX2 up-regulation and PGE₂ production in PC-3 cells, suggesting that radiation-induced COX2 up-regulation is secondary to the production of ROS. The relative increases in COX2 expression and PGE₂ production induced by radiation and H₂O₂ were even greater when PC-3 cells were pretreated with BSO. When the cells were pretreated with α-lipoic acid or NAC for 24 h, both radiation- and H₂O₂-induced COX2 up-regulation and PGE₂ production were markedly inhibited. These results demonstrate that radiation-induced COX2 up-regulation in prostate cancer cells is modulated by the cellular redox status. Radiation-induced increases in ROS levels contribute to the adaptive response of PC-3 cells, resulting in elevated levels of COX2.