Dehydroascorbate (DHA) is the oxidized form of vitamin C that is taken up into cells through the glucose transporter GLUT1. Once inside the cell, DHA undergoes glutathione-mediated reduction to vitamin C. BRAF and KRAS mutant colorectal cancer cells exhibit metabolic features, such as elevated GLUT1 levels, that might make them uniquely sensitive to increased cellular uptake of vitamin C that would deplete available glutathione. Confirming this hypothesis, Yun et al. observed increased cell death of BRAF and KRAS mutant cells and mouse xenografts upon vitamin C treatment due to increased reactive oxygen species (ROS) and reduced glutathione levels. Metabolomics analysis of vitamin C–treated mutant cells revealed enhanced pentose phosphate pathway flux to restore the NADPH and glutathione levels depleted by oxidation of DHA. In addition, enhanced ROS levels decreased glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity owing to increased S-glutathionylation of the active site cysteine and reduced availability of the GAPDH substrate, NAD+. Decreased GAPDH activity results in a buildup of glycolytic intermediates upstream of GAPDH and depletion of ATP, resulting in increased cellular stress. Consistent with the disruption in redox homeostasis, the addition of an antioxidant, N-acetylcysteine, rescued vitamin C–mediated cell death. Overall, these findings reveal an interesting mechanistic rationale explaining the sensitivity of KRAS and BRAF mutant cells to vitamin C.
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Miura, G. Vitamin C attack. Nat Chem Biol 12, 1 (2016). https://doi.org/10.1038/nchembio.1995