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Manganese Superoxide Dismutase Modulates Hypoxia-Inducible Factor-1 Induction via Superoxide

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa

Requests for reprints: Larry W. Oberley, B180 ML, Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242-1181. Phone: 319-335-8015; Fax: 319-335-8039; E-mail: larry-oberley{at}uiowa.edu.

Key Words: hypoxia • MnSOD • HIF-1 • superoxide • siRNA

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays an important role in O₂ homeostasis. Numerous observations suggest that changes in reactive oxygen species affect HIF-1 stabilization and HIF-1 transcriptional activation in many cell types. The antioxidant enzyme manganese superoxide dismutase (MnSOD) modulates the cellular redox environment by converting superoxide (O₂^–) to hydrogen peroxide and dioxygen. Previous results from our group have shown that overexpression of MnSOD in MCF-7 cells alters stabilization of HIF-1 under hypoxic conditions; however, the underlying mechanism(s) is not known. Here, we tested the hypothesis that MnSOD regulates the expression of HIF-1 by modulating the steady-state level of O₂^–. We found that decreasing MnSOD with small interfering RNA in MCF-7 cells resulted in (a) an associated increase in the hypoxic accumulation of HIF-1 immunoreactive protein, (b) a significant increase in the levels of O₂^– (P < 0.01), but (c) no significant change in the steady-state level of H₂O₂. Removal of O₂^– using spin traps (-4-pyridyl-1-oxide-N-tert-butylnitrone and 5,5-dimethyl-1-pyrroline N-oxide) or the O₂^– scavenger Tempol or an SOD mimic (AEOL10113) resulted in a decrease in HIF-1 protein, consistent with the hypothesis that O₂^– is an important molecular effector responsible for hypoxic stabilization of HIF-1. The evidence from both genetic and pharmaceutical manipulation is consistent with our hypothesis that O₂^– can contribute to the stabilization of HIF-1. [Cancer Res 2008;68(8):2781–8]