Manganese superoxide dismutase modulates hypoxia-inducible factor-1 alpha induction via superoxide

Suwimol Kaewpila; Sujatha Venkataraman; Garry R Buettner; Larry W Oberley

doi:10.1158/0008-5472.CAN-07-2635

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Manganese superoxide dismutase modulates hypoxia-inducible factor-1 alpha induction via superoxide

Journal article

Open access

Peer reviewed

Manganese superoxide dismutase modulates hypoxia-inducible factor-1 alpha induction via superoxide

Suwimol Kaewpila, Sujatha Venkataraman, Garry R Buettner and Larry W Oberley

Cancer research (Chicago, Ill.), Vol.68(8), pp.2781-2788

04/15/2008

DOI: 10.1158/0008-5472.CAN-07-2635

PMCID: PMC2633869

PMID: 18413745

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Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays an important role in O(2) homeostasis. Numerous observations suggest that changes in reactive oxygen species affect HIF-1 alpha stabilization and HIF-1 alpha transcriptional activation in many cell types. The antioxidant enzyme manganese superoxide dismutase (MnSOD) modulates the cellular redox environment by converting superoxide (O(2)(*-)) 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 alpha under hypoxic conditions; however, the underlying mechanism(s) is not known. Here, we tested the hypothesis that MnSOD regulates the expression of HIF-1 alpha by modulating the steady-state level of O(2)(*-). 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 alpha immunoreactive protein, (b) a significant increase in the levels of O(2)(*-) (P < 0.01), but (c) no significant change in the steady-state level of H(2)O(2). Removal of O(2)(*-) using spin traps (alpha-4-pyridyl-1-oxide-N-tert-butylnitrone and 5,5-dimethyl-1-pyrroline N-oxide) or the O(2)(*-) scavenger Tempol or an SOD mimic (AEOL10113) resulted in a decrease in HIF-1 alpha protein, consistent with the hypothesis that O(2)(*-) is an important molecular effector responsible for hypoxic stabilization of HIF-1 alpha. The evidence from both genetic and pharmaceutical manipulation is consistent with our hypothesis that O(2)(*-) can contribute to the stabilization of HIF-1 alpha.

Cell Line

Cell Hypoxia - physiology

Superoxide Dismutase - genetics

Breast - cytology

Humans

Breast - physiology

Hydrogen Peroxide - metabolism

Epithelial Cells - physiology

RNA Interference

Hypoxia-Inducible Factor 1, alpha Subunit - metabolism

Superoxides - metabolism

Female

Kinetics

Superoxide Dismutase - metabolism

Details

Title: Subtitle: Manganese superoxide dismutase modulates hypoxia-inducible factor-1 alpha induction via superoxide
Creators: Suwimol Kaewpila - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242-1181, USA
Sujatha Venkataraman
Garry R Buettner
Larry W Oberley
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.68(8), pp.2781-2788
Publisher: United States
DOI: 10.1158/0008-5472.CAN-07-2635
PMID: 18413745
PMCID: PMC2633869
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: CA66081 / NCI NIH HHS CA132850 / NCI NIH HHS R01 CA115438-01A2 / NCI NIH HHS
Language: English
Date published: 04/15/2008
Academic Unit: Radiation Oncology
Record Identifier: 9984047854302771

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