Do low glucose conditions stabilise HIF1 alpha protein in Breast Cancer Cell lines? Specifically in high glycolytic cells like MDA-MB series.
Under normal oxygen conditions, nonmetastatic cells consume less glucose and express low HIF-1α, whereas metastatic cells constitutively express high glycolysis and HIF-1α, suggesting that dysregulation of HIF-1α may induce the Warburg effect.
The recent discovery and study of HIF-1α have implicated a possible molecular mechanism for the Warburg effect in malignant tumors. HIF-1α plays an important role in cellular responses to hypoxia and other stresses. HIF-1α combines with HIF-1β to form a heterodimeric transcription factor that regulates the expression of glycolytic and angiogenic proteins. HIF-1α is constitutively expressed and destabilized in the presence of O2 by proline hydroxylation and is targeted for proteosomal degradation by the von Hippel-Lindau (vH-L) ubiquitin ligase. When accumulated (e.g., under hypoxia), the HIF-1 complex binds hypoxia response elements (HREs; canonically CCATG) in the promoter region of target genes.
To know the relationship between HIF-1α stabilization in oxygenated conditions and the Warburg effect; by comparing glucose transport, lactate production, HIF-1α protein, and HRE-induced transcript levels in metastatic (MDA-mb-435) and nonmetastatic (MCF-7) breast cancer lines. Under a 20% oxygen atmosphere (normoxia), MDA-mb-435 cells have elevated glycolysis, HIF-1α, and HRE transcripts, whereas these parameters are measurably lower in MCF-7 cells. Hypoxia (≤2% oxygen) induced no change in the glycolytic phenotype in MDA-mb-435 cells, whereas HIF-1α, HRE transcripts, and glycolysis were profoundly induced in MCF-7 cells. But due to controversial findings have identified MDA-mb-435 cells with melanoma cells due to the expression of specific melanocyte genes and lack of expression of breast cell line genes in MDA-mb-435 sublines. To account for this possible discrepancy, renal cell carcinoma (RCC4) used, where transfection of the vH-L gene into a vH-L-null line directly modulated HIF-1α levels. Parental RCC4 cells functioned similarly to the MDA-mb-435 and MDA-mb-231 lines by expressing high levels of HIF-1α and exhibiting high glycolysis under normoxic conditions. There was a minimal effect when these cells were switched to hypoxia. Restoration of vH-L activity led to normalization of the HIF-1α response. Under normoxia, RCC4/vH-L cells demonstrated low rates of glycolysis, which subsequently increased in hypoxia.
You may find details in this article: "Hypoxia-Inducible Factor-1α and the Glycolytic Phenotype in Tumors" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1501147/
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