title: The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity.
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.affiliation: From the Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Tian
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Guo
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Longqi
authors.initials: L
authors.lastname: Liu
authors.forename: Fenggong
authors.initials: F
authors.lastname: Cui
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhuang
authors.forename: Xichen
authors.initials: X
authors.lastname: Bao
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.forename: Tung-Liang
authors.initials: TL
authors.lastname: Chung
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Laslett
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.forename: Baoming
authors.initials: B
authors.lastname: Qin
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
mesh_terms: D001205:Ascorbic Acid / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D003603:Cytotoxins / Q000494:pharmacology*; D004249:DNA Damage; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D001205:Ascorbic Acid; D051792:Basic Helix-Loop-Helix Proteins; D003603:Cytotoxins; D051272:Glucose Transporter Type 1; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C495677:SLC2A1 protein, human; C497446:VHL protein, human
keywords: Cancer; DNA Damage; Hypoxia-inducible Factor (HIF); Oxidative Stress; Renal Cancer; Vitamin C; Warburg Effect