Tumor suppressive effects of MnSOD overexpression may involve imbalance in peroxide generation versus peroxide removal

Abstract

Manganese superoxide dismutase (MnSOD) activity is generally lower in cancer cells when compared with their normal cell counterparts. Many studies have shown that replacing the diminished MnSOD activity leads to inhibition of the malignant phenotype. We sought to overexpress MnSOD in a chemically transformed, malignant rat cell line with low endogenous MnSOD activity to determine the effect on the malignant phenotype. After MnSOD cDNA transfection, clonal populations were characterized at the molecular level for protein, RNA, and DNA, as well as for in vitro and in vivo growth and in vivo lung metastasis. MnSOD transfectants, which both under- and overexpressed MnSOD protein, were identified. These transfectants demonstrated variations in glutathione peroxidase and catalase activity levels, indicating differences in peroxide-generating versus peroxide-metabolizing enzymes (antioxidant imbalance); these differences were suggestive of alterations in their abilities to metabolize peroxide when compared with the parental cell line. In addition, these transfectants demonstrated reductions in both in vitro and in vivo growth, as well as a reduction in metastatic potential, which correlated with antioxidant imbalance. These results suggest that the tumor suppressive effect of MnSOD overexpression is in part mediated by an antioxidant imbalance resulting in the reduced capacity to metabolize increased levels of intracellular peroxides.