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

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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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Authors: Vissers, M. C. M., Gunningham, S. P., Morrison, M. J., Dachs, G. U., & Currie, M. J.
Corresponding author: Vissers, Margret C.M.
ORCID: Dachs, Gabi U.
Currie, Margaret J.
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate

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