Mitochondria-targeted antioxidant enzyme activity regulates radioresistance in human pancreatic cancer cells

Carolyn J. Fisher and Prabhat C. Goswami

volume 7 | issue 8

August 2008
Pages: 1271 - 1279

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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 G2-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 G2 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 G2 checkpoint activation and radioresistance in human pancreatic cancer cells.

Authors

Carolyn J. Fisher

Free Radical and Radiation Biology Program, Radiation Oncology Department, University of Iowa, Iowa City, IA

Prabhat C. Goswami