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J. Biol. Chem., Vol. 275, Issue 25, 19241-19249, June 23, 2000

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Overexpression of Catalase in the Mitochondrial or Cytosolic Compartment Increases Sensitivity of HepG2 Cells to Tumor Necrosis Factor--induced Apoptosis^*

Jingxiang Bai and Arthur I. Cederbaum

From the Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029

The sensitivity of HepG2 cells overexpressing catalase in either the cytosolic or mitochondrial compartment to tumor necrosis factor- (TNF-) and cycloheximide was studied. Cells overexpressing catalase in the cytosol (C33 cells) and especially in mitochondria (mC5 cells) were more sensitive to TNF--induced apoptosis than were control cells (Hp cells). The activities of caspase-3 and -8 were increased by TNF-, with the highest activities found in mC5 cells. Sodium azide, an inhibitor of catalase, reduced the increased sensitivity of mC5 and C33 cells to TNF- to the level of toxicity found with control Hp cells. Azide also decreased the elevated caspase-3 activity of mC5 cells. A pan-caspase inhibitor prevented the TNF--induced apoptosis and toxicity produced by catalase overexpression. Addition of H₂O₂ prevented TNF--induced apoptosis and caspase activation, an effect prevented by simultaneous addition of catalase. TNF- plus cycloheximide increased ATP levels, with higher levels in C33 and mC5 cells compared with Hp cells. TNF- did not produce apoptosis in mC5 cells maintained in a low energy state. TNF- signaling was not altered by the overexpression of catalase, as activation of nuclear factor B and AP-1 by TNF- was similar in the three cell lines. These results suggest that catalase, overexpressed in the cytosolic or especially the mitochondrial compartment, potentiates TNF--induced apoptosis and activation of caspases by removal of H₂O₂.

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