title: Radiation-induced cyclooxygenase 2 up-regulation is dependent on redox status in prostate cancer cells.
abstract: 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 PGE(2). 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 (gammaGCS), and the antioxidants alpha-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 alpha-lipoic acid and NAC increased the GSH level and decreased cellular ROS. Both radiation and the oxidant H(2)O(2) had similar effects on COX2 up-regulation and PGE(2) 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 PGE(2) production induced by radiation and H(2)O(2) were even greater when PC-3 cells were pretreated with BSO. When the cells were pretreated with alpha-lipoic acid or NAC for 24 h, both radiation- and H(2)O(2)-induced COX2 up-regulation and PGE(2) 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.
authors.affiliation: Department of Radiation Oncology, Stanford University, School of Medicine, Stanford, California, USA.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Li
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Steinauer
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Dirks
authors.forename: Bryan
authors.initials: B
authors.lastname: Husbeck
authors.forename: Iris
authors.initials: I
authors.lastname: Gibbs
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Knox
mesh_terms: D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000032:analysis; D005978:Glutathione / Q000032:analysis; D006801:Humans; D007527:Isoenzymes / Q000032:analysis*; D008297:Male; D008565:Membrane Proteins; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy*; D017382:Reactive Oxygen Species; D015854:Up-Regulation
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione; D015232:Dinoprostone