Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis.

Peroxiredoxin-3 (Prdx3) is a mitochondrial member of the antioxidant family of thioredoxin peroxidases that uses mitochondrial thioredoxin-2 (Trx2) as a source of reducing equivalents to scavenge hydrogen peroxide (H2O2). Low levels of H2O2 produced by the mitochondria regulate physiological processes, including cell proliferation, while high levels of H2O2 are toxic to the cell and cause apoptosis. WEHI7.2 thymoma cells with stable overexpression of Prdx3 displayed decreased levels of cellular H2O2 and decreased cell proliferation without a change in basal levels of apoptosis. Prdx3-transfected cells showed a marked resistance to hypoxia-induced H2O2 formation and apoptosis. Prdx3 overexpression also protected the cells against apoptosis caused by H2O2, t-butylhydroperoxide, and the anticancer drug imexon, but not by dexamethasone. Thus, mitochondrial Prdx3 is an important cellular antioxidant that regulates physiological levels of H2O2, leading to decreased cell growth while protecting cells from the apoptosisinducing effects of high levels of H2O2.