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DNA Damage and Cellular Stress Responses

Role of Reactive Oxygen Species in Cells Overexpressing Manganese Superoxide Dismutase

Mechanism for Induction of Radioresistance¹

¹ Research Center for Radiation Emergency Medicine and ² National Institute of Radiological Sciences, Chiba, Japan; and
³ Diversity and Fractal Science, the Graduate School of Science and Technology, Chiba University, Chiba, Japan

Requests for reprints: Makoto Akashi, The Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. Phone: 81-43-206-3122; Fax: 81-43-284-1736. E-mail: akashi{at}nirs.go.jp

Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide anions (O₂^-) into hydrogen peroxide (H₂O₂). We altered the intracellular status of reactive oxygen species by introducing human MnSOD cDNA into the human ovarian cancer cell line SK-OV-3. The overexpression of MnSOD inhibited cell growth and induced a concomitant increase in the level of H₂O₂ in SK-OV-3 cells. The cells overexpressing MnSOD were more resistant to irradiation than parental cells. MnSOD overexpression shortened the G₂-M duration in irradiated cells. Either inhibition of p38 mitogen-activated protein kinase (p38MAPK) or scavenging free radicals blocked the induction of radioresistance by MnSOD and also abolished the shortening of the G₂-M duration with concomitant inhibition of p38MAPK phosphorylation. Irradiation increased the generation of H₂O₂ even more in these transfectants. These results suggest that the accumulated H₂O₂ potentiated the activation of p38MAPK after irradiation in cells overexpressing MnSOD, which led to the protection of cells from irradiation-mediated cell death through the G₂-M checkpoint. SK-OV-3 cells had no constitutive expression of p53, and the overexpression of MnSOD and/or irradiation did not induce p53 or p21^WAF1, which causes cell cycle arrest. Thus, our results suggest that MnSOD alters the cell cycle progression of irradiated cells independently of p53 and p21^WAF1.

Key Words: Manganese superoxide dismutase (MnSOD) • reactive oxygen species (ROS) • p38MAPK • radioresistance

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