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Title: High glucose concentrations attenuate hypoxia-inducible factor-1{alpha} expression and signaling in non-tumor cells

Abstract

Hypoxia-inducible factor (HIF) is the major transcription factor mediating adaption to hypoxia e.g. by enhancing glycolysis. In tumor cells, high glucose concentrations are known to increase HIF-1{alpha} expression even under normoxia, presumably by enhancing the concentration of tricarboxylic acid cycle intermediates, while reactions of non-tumor cells are not well defined. Therefore, we analyzed cellular responses to different glucose concentrations in respect to HIF activation comparing tumor to non-tumor cells. Using cells derived from non-tumor origin, we show that HIF-1{alpha} accumulation was higher under low compared to high glucose concentrations. Low glucose allowed mRNA expression of HIF-1 target genes like adrenomedullin. Transfection of C{sub 2}C{sub 12} cells with a HIF-1{alpha} oxygen-dependent degradation domaine-GFP fusion protein revealed that prolyl hydroxylase (PHD) activity is impaired at low glucose concentrations, thus stabilizing the fusion protein. Mechanistic considerations suggested that neither O{sub 2} redistribution nor an altered redox state explains impaired PHD activity in the absence of glucose. In order to affect PHD activity, glucose needs to be metabolized. Amino acids present in the medium also diminished HIF-1{alpha} expression, while the addition of fatty acids did not. This suggests that glucose or amino acid metabolism increases oxoglutarate concentrations, which enhances PHD activity in non-tumor cells.more » Tumor cells deprived of glutamine showed HIF-1{alpha} accumulation in the absence of glucose, proposing that enhanced glutaminolysis observed in many tumors enables these cells to compensate reduced oxoglutarate production in the absence of glucose.« less

Authors:
 [1];  [2];  [1]
  1. Institute of Biochemistry I/ZAFES (Germany)
  2. Zentrallabor, Goethe-University, 60590 Frankfurt am Main (Germany)
Publication Date:
OSTI Identifier:
22212069
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 316; Journal Issue: 7; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANOXIA; CARBONYLS; CONCENTRATION RATIO; CYANIDES; GLUCOSE; GLUTAMINE; GLYCOLYSIS; HYDROXYLASES; MESSENGER-RNA; NEOPLASMS; TRANSCRIPTION FACTORS; TUMOR CELLS

Citation Formats

Dehne, Nathalie, Hintereder, Gudrun, and Bruene, Bernhard. High glucose concentrations attenuate hypoxia-inducible factor-1{alpha} expression and signaling in non-tumor cells. United States: N. p., 2010. Web. doi:10.1016/J.YEXCR.2010.02.019.
Dehne, Nathalie, Hintereder, Gudrun, & Bruene, Bernhard. High glucose concentrations attenuate hypoxia-inducible factor-1{alpha} expression and signaling in non-tumor cells. United States. https://doi.org/10.1016/J.YEXCR.2010.02.019
Dehne, Nathalie, Hintereder, Gudrun, and Bruene, Bernhard. 2010. "High glucose concentrations attenuate hypoxia-inducible factor-1{alpha} expression and signaling in non-tumor cells". United States. https://doi.org/10.1016/J.YEXCR.2010.02.019.
@article{osti_22212069,
title = {High glucose concentrations attenuate hypoxia-inducible factor-1{alpha} expression and signaling in non-tumor cells},
author = {Dehne, Nathalie and Hintereder, Gudrun and Bruene, Bernhard},
abstractNote = {Hypoxia-inducible factor (HIF) is the major transcription factor mediating adaption to hypoxia e.g. by enhancing glycolysis. In tumor cells, high glucose concentrations are known to increase HIF-1{alpha} expression even under normoxia, presumably by enhancing the concentration of tricarboxylic acid cycle intermediates, while reactions of non-tumor cells are not well defined. Therefore, we analyzed cellular responses to different glucose concentrations in respect to HIF activation comparing tumor to non-tumor cells. Using cells derived from non-tumor origin, we show that HIF-1{alpha} accumulation was higher under low compared to high glucose concentrations. Low glucose allowed mRNA expression of HIF-1 target genes like adrenomedullin. Transfection of C{sub 2}C{sub 12} cells with a HIF-1{alpha} oxygen-dependent degradation domaine-GFP fusion protein revealed that prolyl hydroxylase (PHD) activity is impaired at low glucose concentrations, thus stabilizing the fusion protein. Mechanistic considerations suggested that neither O{sub 2} redistribution nor an altered redox state explains impaired PHD activity in the absence of glucose. In order to affect PHD activity, glucose needs to be metabolized. Amino acids present in the medium also diminished HIF-1{alpha} expression, while the addition of fatty acids did not. This suggests that glucose or amino acid metabolism increases oxoglutarate concentrations, which enhances PHD activity in non-tumor cells. Tumor cells deprived of glutamine showed HIF-1{alpha} accumulation in the absence of glucose, proposing that enhanced glutaminolysis observed in many tumors enables these cells to compensate reduced oxoglutarate production in the absence of glucose.},
doi = {10.1016/J.YEXCR.2010.02.019},
url = {https://www.osti.gov/biblio/22212069}, journal = {Experimental Cell Research},
issn = {0014-4827},
number = 7,
volume = 316,
place = {United States},
year = {Thu Apr 15 00:00:00 EDT 2010},
month = {Thu Apr 15 00:00:00 EDT 2010}
}