The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity

Tian W, Wang Y, Xu Y, Guo X, Wang B, Sun L, Liu L, Cui F, Zhuang Q, Bao X, Schley G, Chung TL, Laslett AL, Willam C, Qin B, Maxwell PH, Esteban MA (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Publisher: American Society for Biochemistry and Molecular Biology

Book Volume: 289

Pages Range: 3339-51

Journal Issue: 6

DOI: 10.1074/jbc.M113.538157

Abstract

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.

Authors with CRIS profile

Carsten Willam Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Chinese Academy of Sciences (CAS) / 中国科学院 CN China (CN) Commonwealth Scientific and Industrial Research Organisation (CSIRO) AU Australia (AU) University of Cambridge GB United Kingdom (GB)

How to cite

APA:

Tian, W., Wang, Y., Xu, Y., Guo, X., Wang, B., Sun, L.,... Esteban, M.A. (2014). The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity. Journal of Biological Chemistry, 289(6), 3339-51. https://doi.org/10.1074/jbc.M113.538157

MLA:

Tian, Weihua, et al. "The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity." Journal of Biological Chemistry 289.6 (2014): 3339-51.

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