title: Chronic hypoxia leads to a glycolytic phenotype and suppressed HIF-2 signaling in PC12 cells.
abstract: BACKGROUND
  Along with other regulators of cell metabolism, hypoxia-inducible factors HIF-1 and HIF-2 differentially regulate cell adaptation to hypoxia. Switches in HIF-1/HIF-2 signaling in chronic hypoxia have not been fully investigated.
  
  
  METHODS
  Proliferation, viability, apoptosis, neuronal and bioenergetic markers, mitochondrial function, respiration, glycolysis, HIF signalling, responses to O2 and glucose deprivation (OGD) were examined using tumor PC12 and SH-SY5Y cells continuously grown at 3% O2.
  
  
  RESULTS
  Hypoxic PC12 cells (H-cells) exhibit reduced proliferation and histone H4 acetylation, NGF-independent differentiation, activation of AMPK, inhibition of Akt, altered mitochondria and response to NGF. Cellular cytochrome c is increased with no effect on apoptosis. Reduction in respiration has minor effect on cellular ATP which is maintained through activated uptake (GLUT1) and utilization (HK2, PFK2) of glucose. H-cells exhibit resistance to OGD linked to increased glycogen stores. HIF-2alpha protein is decreased without changes in mRNA. Unlike HIF-1alpha, HIF-2alpha is not stabilized pharmacologically or by O2 deprivation. Capacity for HIF-2alpha stabilization is partly restored when H-cells are cultured at normoxia. In low-respiring SH-SY5Y cells cultured under the same conditions HIF-2alpha stabilization and energy budget are not affected.
  
  
  CONCLUSIONS
  In chronically hypoxic PC12 cells glycolytic energy budget, increased energy preservation and low susceptibility to OGD are observed. HIF-2alpha no longer orchestrates adaptive responses to anoxia.
  
  
  CONCLUSIONS
  Demonstrated switch in HIF-1/HIF-2 signaling upon chronic hypoxia can facilitate cell survival in energy crisis, by regulating balance between energy saving and decrease in proliferation, on one hand and active cell growth and tumor expansion, on the other.
authors: Biochemistry Department, University College Cork, Cork, Ireland. a.zhdanov@ucc.ie
authors: Alexander V
authors: AV
authors: Zhdanov
authors: Ruslan I
authors: RI
authors: Dmitriev
authors: Anna V
authors: AV
authors: Golubeva
authors: Svetlana A
authors: SA
authors: Gavrilova
authors: Dmitri B
authors: DB
authors: Papkovsky
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D049109:Cell Proliferation; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D016716:PC12 Cells; D055550:Protein Stability / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D055372:AMP-Activated Protein Kinases; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020932:Nerve Growth Factor; D010100:Oxygen; D051057:Proto-Oncogene Proteins c-akt; D000099162:Endothelial PAS Domain-Containing Protein 1; C497444:Hif1a protein, rat