title: Mitochondria-targeted antioxidant enzyme activity regulates radioresistance in human pancreatic cancer cells.
abstract: In recent years, cellular redox environment gained significant attention as a critical regulator of cellular responses to oxidative stress. Cellular redox environment is a balance between production of reactive oxygen species and their removal by antioxidant enzymes. We investigated the hypothesis that mitochondrial antioxidant enzyme activity regulates radioresistance in human pancreatic cancer cells. Vector-control and manganese superoxide dismutase (MnSOD) overexpressing human pancreatic cancer cells were irradiated and assayed for cell survival and activation of the G(2)-checkpoint pathway. Increased MnSOD activity significantly increased cell survival following irradiation with 6 Gy of gamma-radiation (p < 0.05). The MnSOD overexpressing irradiated cells also revealed 3-4 folds increase in the percentage of G(2) cells compared to irradiated vector-control. Furthermore, MnSOD overexpressing irradiated cells exhibited increased loss of phosphorylated histone H2AX protein levels. The radiation-induced increase in cyclin B1 protein levels in irradiated vector-control cells was suppressed in irradiated MnSOD overexpressing cells. Mitochondria-targeted catalase overexpression increased the survival of irradiated cells. These results support the hypothesis that mitochondrial antioxidant enzyme activity and mitochondria-generated reactive oxygen species-signaling (superoxide and hydrogen peroxide) could regulate radiation-induced G(2) checkpoint activation and radioresistance in human pancreatic cancer cells.
authors.affiliation: Free Radical and Radiation Biology Program, Radiation Oncology Department, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Fisher
authors.forename: Prabhat C
authors.initials: PC
authors.lastname: Goswami
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000528:radiation effects; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004307:Dose-Response Relationship, Radiation; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase