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Nitric Oxide Enhances the Manganese Superoxide Dismutase-dependent Suppression of Proliferation in HT-1080 Fibrosarcoma Cells¹

Departments of Biochemistry and Molecular Biology [J. A. M., A. M. R.] and Microbiology, Immunology, and Molecular Genetics [J. E. M.], Albany Medical College, Albany, New York 12208; Montfiore Medical Center, Department of Radiation Oncology, Bronx, New York [R. P. M.]; and Ethel Percy Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089-0191 [K. J. A. D.]

The overexpression of manganese superoxide dismutase (MnSOD), an enzyme that catalyzes the removal of superoxide (O₂) from the mitochondria, has been shown to be closely associated with tumor regression in vivo and loss of the malignant phenotype in vitro. To investigate the mechanism by which MnSOD overexpression mediates this reversal, we have established 29 independent, clonal MnSOD-overexpressing HT-1080 fibrosarcoma cells. MnSOD activity is inversely correlated with cell proliferation in our cell lines. Incubating cells in 3% oxygen can prevent the inhibition of cellular proliferation mediated by MnSOD, suggesting that oxygen is a prerequisite component of the MnSOD-dependent proliferative inhibition. Confocal laser microscopy was used in combination with the oxidant-sensitive fluorescent dyes dihydrorhodamine-123, dihydroethidium, and 2',7'-dichlorodihydrofluorescein diacetate to determine the oxidizing capacity of the MnSOD-overexpressing cells. When compared with parental or control cell lines, there was a significant decrease in the rate of oxidation of the fluorophores in the MnSOD-overexpressing cell lines. Thus, an increase in the oxidizing capacity of the cells does not appear to mediate the inhibition of proliferation associated with MnSOD overexpression. Superoxide dismutase has also been shown to enhance the cytotoxic activity of NO· toward tumor cells. In this study, we have shown that MnSOD overexpression enhances the cytostatic action of the NO· donors, sodium nitroprusside, 3-morpholinosydnonomine, and (Z)-1-[2-aminethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate in a dose-dependent manner. In addition, the NO· toxicity is blocked by oxyhemoglobin, a NO· scavenger. Our findings suggest that NO· may play a role in the reversal of tumorigenicity associated with MnSOD overexpression.

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