The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase

Manganese-containing superoxide dismutase (MnSOD) is an essential primary a ntioxidant enzyme that converts superoxide radical to hydrogen peroxide and molecular oxygen within the mitochondrial matrix. Cytosolic glutathione pe roxidase (GPX) converts hydrogen peroxide into water, MnSOD is reduced in a variety of tumor types and has been proposed to be a new kind of tumor sup pressor gene, but the mechanism(s) by which MnSOD suppresses malignancy is unclear. According to the enzymatic reactions catalyzed by MnSOD and cytoso lic GPX, change in the cellular redox status, especially change attributabl e to accumulation of hydrogen peroxide or other hydroperoxides, is a possib le reason to explain the suppression of tumor growth observed in MnSOD-over expressing cells. To test this possible mechanism, we transfected human cyt osolic GPX cDNA into human glioma cells overexpressing MnSOD. The results s howed that GPX overexpression not only reversed the tumor cell growth inhib ition caused by MnSOD overexpression but also altered the cellular contents of total glutathione, reduced glutathione, oxidized glutathione, and Intra cellular reactive oxygen species, Overexpression of GPX also inhibited degr adation of the inhibitory subunit alpha of nuclear factor-kappa B. These re sults suggest that hydrogen peroxide or other hydroperoxides appear to be k ey reactants in the tumor suppression by MnSOD overexpression, and growth i nhibition correlates with the intracellular redox status. This work suggest s that manipulations that inhibit peroxide removal should enhance the tumor suppressive effect of MnSOD overexpression.