The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity
Open accessAbstract
Megadose vitamin C (Vc) is one of the most enduring alternative treatments for diverse human diseases and is deeply engrafted in popular culture. Preliminary studies in the 1970s described potent effects of Vc on prolonging the survival of patients with terminal cancer, but these claims were later criticized. An improved knowledge of the pharmacokinetics of Vc and recent reports using cancer cell lines have renewed the interest in this subject. Despite these findings, using Vc as an adjuvant for anticancer therapy remains questionable, among other things because there is no proper mechanistic understanding. Here, we show that a Warburg effect triggered by activation of the hypoxia-inducible factor (HIF) pathway greatly enhances Vc-induced toxicity in multiple cancer cell lines, including von Hippel-Lindau (VHL)-defective renal cancer cells. HIF increases the intracellular uptake of oxidized Vc through its transcriptional target glucose transporter 1 (GLUT1), synergizing with the uptake of its reduced form through sodium-dependent Vc transporters. The resulting high levels of intracellular Vc induce oxidative stress and massive DNA damage, which then causes metabolic exhaustion by depleting cellular ATP reserves. HIF-positive cells are particularly sensitive to Vc-induced ATP reduction because they mostly rely on the rather inefficient glycolytic pathway for energy production. Thus, our experiments link Vc-induced toxicity and cancer metabolism, providing a new explanation for the preferential effect of Vc on cancer cells.
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Normoxic VHL-deficient cells had more GLUT1 than VHL-proficient cells, which increased uptake of ascorbate-derived DHA, raising ROS and causing death; knocking down GLUT1 made them resistant to vitamin C toxicity.
“the higher levels of GLUT1, a HIF1α downstream target, in normoxic VHL-deficient cells than in VHL-proficient cells facilitated increased uptake of ascorbate-derived DHA, leading to increased generation of ROS and cell death. In line with this, GLUT1 knockdown in VHL-deficient RCC cells conferred resistance to vitamin-C-induced toxicity.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [52]
In normoxia, vitamin C kills VHL-deficient RCC cells but not isogenic VHL-proficient cells.
“VHL-deficient RCC cells undergo cell death when exposed to vitamin C in normoxia, in contrast to isogenic VHL-proficient cells52.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [52]
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- Authors
- Tian, W., Wang, Y., Xu, Y., Guo, X., Wang, B., Sun, L., Liu, L., Cui, F., Zhuang, Q., Bao, X., Schley, G., Chung, T.-L., Laslett, A. L., Willam, C., Qin, B., Maxwell, P. H., & Esteban, M. A.
- Affiliations
- University of Science and Technology of China (CN)
- Chinese Academy of Sciences (CN)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- Wellcome Trust (GB)
- Corresponding author
- Esteban, Miguel A.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 289
- Issue
- 6
- Pages
- 3339-3351
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3916538
- OpenAlex
- W1999839463
- Cited by
- 59
- References
- 73
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 4 · 2018: 10 · 2017: 7 · 2016: 3 · 2015: 8 · 2014: 1
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (100140, 096956/Z/11/Z, 96956)
- National Natural Science Foundation of China
- 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 › Cancer and biochemical research
- Keywords
- vitamin C, hypoxia-inducible factor, Warburg effect, cancer metabolism, glucose transporter 1, sodium-dependent vitamin C transporters, oxidative stress, DNA damage, ATP depletion, glycolysis, VHL, kidney cancer
- MeSH terms
- Ascorbic Acid, Cytotoxins, DNA Damage, HeLa Cells, Humans, Neoplasms, Signal Transduction, Oxidative Stress, Glucose Transporter Type 1, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein
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