Role of reactive oxygen species in cells overexpressing manganese superoxide dismutase: mechanism for induction of radioresistance.
Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide anions (O(2)(-)) into hydrogen peroxide (H(2)O(2)). 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 H(2)O(2) in SK-OV-3 cells. The cells overexpressing MnSOD were more resistant to irradiation than parental cells. MnSOD overexpression shortened the G(2)-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 G(2)-M duration with concomitant inhibition of p38MAPK phosphorylation. Irradiation increased the generation of H(2)O(2) even more in these transfectants. These results suggest that the accumulated H(2)O(2) 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 G(2)-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).
Takada
Yasunari
Y
Research Center for Radiation Emergency Medicine, Chiba, Japan.
Hachiya
Misao
M
Park
Sang-Hee
SH
Osawa
Yoshiaki
Y
Ozawa
Toshihiko
T
Akashi
Makoto
M
D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D016195:G2 Phase; D005822:Genetic Vectors; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis; D018384:Oxidative Stress; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011836:Radiation Tolerance; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases