The Enzyme MnSOD Suppresses Malignant Breast Cell Growth by Preventing HIF-1 Activation
Abstract
Hypoxia inducible factor-1 (HIF-1) is a transcription factor that governs cellular responses to reduced O2 availability by mediating crucial homeostatic processes. The degradation of HIF-1 alpha subunit is redox regulated. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that can modulate cellular redox environment. Here we show that MnSOD suppresses hypoxic accumulation of HIF-1 alpha protein. This suppression is biphasic depending on MnSOD activity. At low levels of MnSOD activity, HIF-1 alpha protein accumulates under hypoxic conditions in human breast carcinoma MCF-7 cells. At moderate levels of MnSOD activity (2-to 6-fold increase compared to parent cells), these accumulations are blocked. However, at higher levels of MnSOD activity (>6-fold increase), accumulation of HIF-1 alpha protein is again observed and the HIF-1 alpha protein level increases with increasing MnSOD activity. This biphasic modulation can be observed under both 1% O2 and 4% 02. Hypoxic induction of vascular endothelial growth factor (VEGF), a known HIF-1 targeted gene, is also suppressed by elevated MnSOD activity and its expression levels reflected the protein levels of HIF-1 alpha. These observations demonstrate that HIF-1 alpha accumulation is modulated not only by the levels of dioxygen but also the antioxidant enzyme MnSOD.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA429516
Entities
People
- Garry Buettner
- Min Wang
Organizations
- University of Iowa