Vitamin C Targets GAPDH to Kill KRAS- and BRAF-Mutant Cancer Cells

About half of colorectal cancers harbor activating mutations in either KRAS or BRAF. KRAS- and BRAF-mutant tumors exhibit increased glucose uptake and expression of the glucose transporter GLUT1 (also known as SLC2A1), suggesting that exploiting the reliance of these tumors on glycolysis may represent a possible therapeutic strategy. GLUT1 also transports dehydroascorbate (DHA), the oxidized form of vitamin C, into the cell, where it is reduced to vitamin C in a process that consumes the antioxidant glutathione (GSH). To test the hypothesis that increased DHA uptake would disrupt redox homeostasis and kill KRAS- or BRAF-mutant cells, Yun and colleagues treated a panel of colorectal cancer cell lines with vitamin C. Although both wild-type and mutant colorectal cancer cells preferentially took up DHA over vitamin C via the GLUT1 receptor, the increased GLUT1 expression in KRAS- and BRAF-mutant cells resulted in enhanced vitamin C uptake compared with wild-type cells. Vitamin C treatment was selectively cytotoxic in KRAS- and BRAF-mutant cells in vitro, and reduced tumor growth in vivo in xenografts and the Apc;Kras^G12D transgenic model of intestinal cancer. In contrast, whereas GLUT1 overexpression was sufficient to increase vitamin C uptake in wild-type cells, it did not render them sensitive to the cytotoxic effects, suggesting that oncogene-induced metabolic reprogramming is required for vitamin C–mediated toxicity. Mechanistically, DHA uptake and reduction to vitamin C depleted cellular GSH levels, resulting in increased reactive oxygen species (ROS) in KRAS- and BRAF-mutant cells. Furthermore, vitamin C induced ROS-dependent inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) via posttranslational modifications and depletion of NAD⁺ substrate, leading to inhibition of glycolysis, decreased ATP levels, and cell death. Taken together, these results provide a mechanism for the selective killing of KRAS- and BRAF-mutant cancer cells by vitamin C and support continued investigation of vitamin C in human tumors.

Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 2015;350:1391–6.

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