Chronic hypoxia leads to a glycolytic phenotype and suppressed HIF-2 signaling in PC12 cells |
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Authors: | Alexander V Zhdanov Ruslan I Dmitriev Anna V Golubeva Svetlana A Gavrilova Dmitri B Papkovsky |
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Institution: | 1. Biochemistry Department, University College Cork, Cavanagh Pharmacy Building, College Road, Cork, Ireland;2. Alimentary Pharmabiotic Centre, University College Cork, Bioscience Institute, Western Road, Cork, Ireland;3. Faculty of Fundamental Medicine, Moscow State University, 31-5 Lomonosovsky Prospekt, Moscow 117192, Russia |
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Abstract: | BackgroundAlong 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.MethodsProliferation, 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.ResultsHypoxic 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.ConclusionsIn 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.General significanceDemonstrated 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. |
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Keywords: | Chronic hypoxia Cell energy budget HIF-2 Mitochondria Oxygen and glucose deprivation PC12 cells |
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