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Cited by 125Cancer, Hypoxia, and MetabolismVitamin C and Antioxidants ResearchAngiogenesis and VEGF in Cancer

The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.

Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate

Vissers, Margret C.M., Gunningham, Sarah P., Morrison, Mary J., Dachs, Gabi U., Currie, Margaret J.·2007·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2006.11.023
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Abstract

Control of the transcription factor hypoxia inducible factor (HIF)-1 is mediated by hydroxylation by proline and asparagine hydroxylases. These enzymes require ascorbate for optimal activity, but little attention has been given to the effect of ascorbate on HIF-1 activation. Furthermore, cells in culture are ascorbate deficient. We investigated the effect of intracellular ascorbate on HIF-1alpha protein levels and on HIF-1-mediated gene expression in two human primary cell lines (umbilical vein endothelial cells and skin fibroblasts) and one human cancer cell line (A431 epithelial cells). Under normal culture conditions the cells contained no ascorbate and adding ascorbate to the medium increased intracellular concentrations in a dose-dependent manner. A basal level of HIF-1alpha detected in nonsupplemented cells under normoxic conditions disappeared when 10 microM ascorbate was added to the medium. Induction of HIF-1alpha by hypoxia (1% O(2)) or by CoCl(2) was markedly inhibited by ascorbate and loading with physiological levels resulted in almost complete reversal of HIF-1alpha stabilisation. Gene expression was similarly affected, with VEGF mRNA and GLUT-1 up-regulation being inhibited by ascorbate. Hence intracellular ascorbate is a major regulator of the hypoxic response in normal cells and optimal levels of this vitamin will have a profound effect on HIF-1-regulated processes.

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Metadata

Authors
Vissers, M. C. M., Gunningham, S. P., Morrison, M. J., Dachs, G. U., & Currie, M. J.
Corresponding author
Vissers, Margret C.M.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2007-03
Volume
42
Issue
6
Pages
765-772
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2006.11.023
OpenAlex
W1984689645
Cited by
125
References
56
Citations by year
2026: 4 · 2025: 3 · 2024: 9 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 9 · 2018: 4 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 15 · 2013: 8 · 2012: 7
FWCI
1.95
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Chinese Academy of Agricultural Sciences
  • Health Research Council of New Zealand
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
hypoxia-inducible factor-1α, vitamin C, prolyl hydroxylase, asparaginyl hydroxylase, HIF-1α stabilization, hypoxia response, vascular endothelial growth factor, GLUT1, umbilical vein endothelial cells, dermal fibroblasts, cobalt chloride, normoxia
MeSH terms
Hypoxia, Ascorbic Acid, Cells, Cultured, Dose-Response Relationship, Drug, Endothelium, Vascular, Fibroblasts, Gene Expression Regulation, Humans, RNA, Messenger, Blotting, Western, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Glucose Transporter Type 1, Hypoxia-Inducible Factor 1, alpha Subunit

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