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Manganese superoxide dismutase suppresses hypoxic induction of hypoxia-inducible factor-1α and vascular endothelial growth factor

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that governs cellular responses to reduced O2 availability by mediating crucial homeostatic processes. HIF-1 is composed of an HIF-1α subunit and an HIF-1β subunit. HIF-1α is degraded following enzyme-dependent hydroxylation of prolines of HIF-1α in the presence of molecular oxygen, Fe2+, α-ketoglutarate, and ascorbate. These cofactors contribute to the redox environment of cells. The antioxidant enzyme manganese superoxide dismutase (MnSOD) also modulates the cellular redox environment. Here we show that MnSOD suppressed hypoxic accumulation of HIF-1α protein in human breast carcinoma MCF-7 cells. This suppression was biphasic depending on MnSOD activity. At low levels of MnSOD activity, HIF-1α protein accumulated under hypoxic conditions. At moderate levels of MnSOD activity (two- to six-fold increase compared to parent cells), these accumulations were blocked. However, at higher levels of MnSOD activity (>6-fold increase), accumulation of HIF-1α protein was again observed. This biphasic modulation was observed under both 1 and 4% O2. Coexpression of mitochondrial hydrogen peroxide-removing proteins prevented the accumulation of HIF-1α protein in cells with high levels of MnSOD; this effect demonstrates that the restabilization of HIF-1α observed in high MnSOD overexpressors is probably due to hydrogen peroxide, most likely produced from MnSOD. Hypoxic induction of vascular endothelial growth factor (VEGF) protein was also suppressed by elevated MnSOD activity and its levels reflected HIF-1α protein levels. These observations demonstrated that HIF-1α accumulation and VEGF expression could be modulated by the antioxidant enzyme MnSOD.

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Abbreviations

HIF-1:

hypoxia-inducible factor-1

MnSOD:

manganese superoxide dismutase

MOI:

multiplicity of infection

NBT:

nitroblue tetrazolium

ROS:

reactive oxygen species

VEGF:

vascular endothelial growth factor

VHL:

von Hippel–Lindau

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Acknowledgements

We thank Dr Douglas Trask for generously giving us the VEGF-A primers. We thank Ms Kellie B Goranson for her excellent editorial assistance. This research was supported by a University of Iowa Carver Trust Medical Research Initiative Grant and NIH Grants CA66081 and CA81090. MW was partially supported by a Department of Defense predoctoral traineeship award from the Breast Cancer Research Program (DAMD17-02-1-0425).

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Correspondence to Larry W Oberley.

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Wang, M., Kirk, J., Venkataraman, S. et al. Manganese superoxide dismutase suppresses hypoxic induction of hypoxia-inducible factor-1α and vascular endothelial growth factor. Oncogene 24, 8154–8166 (2005). https://doi.org/10.1038/sj.onc.1208986

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Keywords

  • HIF-1
  • VEGF
  • angiogenesis
  • hypoxia
  • MnSOD

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