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PMID:10511315

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Citation

Melendez, JA, Melathe, RP, Rodriguez, AM, Mazurkiewicz, JE and Davies, KJ (1999) Nitric oxide enhances the manganese superoxide dismutase-dependent suppression of proliferation in HT-1080 fibrosarcoma cells. Cell Growth Differ. 10:655-64

Abstract

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.

Links

PubMed

Keywords

Cell Division/drug effects; Cell Division/physiology; Cell Hypoxia/physiology; Fibrosarcoma/metabolism; Gene Expression Regulation, Enzymologic; Humans; Mitochondria/enzymology; Nitric Oxide/metabolism; Nitric Oxide Donors/pharmacology; Nitroso Compounds/pharmacology; Oxidation-Reduction; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism; Tumor Cells, Cultured/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SODM

located_in

GO:0005759: mitochondrial matrix

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SODM

enables

GO:0030145: manganese ion binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete


See also

References

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