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DNA Damage and Cellular Stress Responses

Increased Expression of Mitochondrial Peroxiredoxin-3 (Thioredoxin Peroxidase-2) Protects Cancer Cells Against Hypoxia and Drug-Induced Hydrogen Peroxide-Dependent Apoptosis¹

Arizona Cancer Center, University of Arizona, Tucson, AZ

Requests for reprints: Garth Powis, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724-5024. Phone: (520) 626-6704; Fax: (520) 626-4848. E-mail: gpowis{at}azcc.arizona.edu

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 apoptosis-inducing effects of high levels of H₂O₂.

Key Words: peroxiredoxin-3 • mitochondria • hydrogen peroxide • hypoxia • apoptosis

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