The Role of Cellular Glutathione Peroxidase Redox Regulation in the Suppression of Tumor Cell Growth by Manganese Superoxide Dismutase
2000
Manganese-containing superoxide dismutase (MnSOD) is an essential
primary antioxidant enzyme that converts superoxide radical to hydrogen
peroxide and molecular oxygen within the mitochondrial matrix.
Cytosolic glutathione peroxidase (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 suppressor gene, but the
mechanism(s) by which MnSOD suppresses malignancy is unclear. According
to the enzymatic reactions catalyzed by MnSOD and cytosolic GPX, change
in the cellular redox status, especially change attributable to
accumulation of hydrogen peroxide or other hydroperoxides, is a
possible reason to explain the suppression of tumor growth observed in
MnSOD-overexpressing cells. To test this possible mechanism, we
transfected human cytosolic GPX cDNA into human glioma cells
overexpressing MnSOD. The results showed that GPX overexpression not
only reversed the tumor cell growth inhibition caused by MnSOD
overexpression but also altered the cellular contents of total
glutathione, reduced glutathione, oxidized glutathione, and
intracellular reactive oxygen species. Overexpression of GPX also
inhibited degradation of the inhibitory subunit α of nuclear
factor-κB. These results suggest that hydrogen peroxide or
other hydroperoxides appear to be key reactants in the tumor
suppression by MnSOD overexpression, and growth inhibition correlates
with the intracellular redox status. This work suggests that
manipulations that inhibit peroxide removal should enhance the tumor
suppressive effect of MnSOD overexpression.
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