The Enzyme MnSOD Suppresses Malignant Breast Cell Growth by Preventing HIF-1 Activation
Annuary summary rept. 18 Apr 2003-17 Apr 2004
IOWA UNIV IOWA CITY
Pagination or Media Count:
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.
- Medicine and Medical Research