C93
Glycolytic phenotype and growth properties preserved in a HIF-1β deficient tumor cell line
Monika Golinska1, Helen Troy2, John Griffiths1
1Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK, 2Institute of Cancer Research, Sutton, UK
Cells respond to low oxygen levels by activating a HIF-1 transcription factor, which then upregulates the expression of a variety of genes including those controlling glucose metabolism, angiogenesis and cell growth. HIF-1 expression is often upregulated in cancer, and it is also activated as tumors are often hypoxic; both effects are thought to contribute to the altered metabolism of tumour cells.
Our group has studied glucose and energy metabolism in a HIF-1β deficient hepatoma mouse model (mutant), in which active HIF-1 cannot be formed as the oxygen-sensitive HIF-1α molecule cannot bind to its HIF-1β partner. Mutant cells unable to active HIF-1 should not be able to upregulate glycolysis, and indeed we have found that their glycolytic enzymes are downregulated. However, we have observed that the mutant cells have the same rate of glucose uptake and the same rate of lactate production, both in normoxia and hypoxia. Furthermore, when grown as xenografted tumours, mutant catches up with the wild type after an initial lag phase and then grows at a similar rate. VEGF production is higher in the wild-type tumors when they are small but is the same in larger tumors. Interestingly, expression levels of cMyc, NFkB or Akt proteins, which could upregulate glycolysis independently of HIF, show upregulation in the wild type but not (as expected) in the mutant.
We are trying to explain what enables the HIF-1β deficient tumors to grow and metabolise at the same rate as wild type do.
