Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
By Jihye Yun, Edouard Mullarky, Changyuan Lu, Kaitlyn N. Bosch, A. Kavalier, Keith D. Rivera, Jatin Roper, I. I. C. Chio, Eugenia G. Giannopoulou, C. Rago and 10 more. Science, 2015
849 citations recorded by the source corpus.
Getting all stressed out by vitamin C Few experimental cancer therapies have incited as much debate as vitamin C. Yet the mechanistic effect of vitamin C on cancer cells is still poorly understood. Yun et al. studied human colorectal cancer cells with KRAS or BRAF mutations and found that they “handle” vitamin C in a different way than other cells, ultimately to their detriment (see the Perspective by Reczek and Chandel). Because a certain receptor is up-regulated in the mutant cells, they take up the oxidized form of vitamin C (dehydroascorbate). This leads to oxidative stress, inactivation of a glycolytic enzyme required by the mutant cells for growth, and finally cell death. Whether the selective toxicity of vitamin C to these mutant cells can be exploited therapeutically remains unclear. Science, this issue p. 1391; see also p. 1317 Cancer cells with certain mutations take up the oxidized form of vitamin C, which fatally disrupts their metabolism. [Also see Perspective by Reczek and Chandel] More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/KrasG12D mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.
Subfields: Nutrition and Dietetics, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/42c3e1bc8eddec3d0c1e7d8794521bbbb6faf89e
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Nutrition and Dietetics
In Pathology and Forensic Medicine
Citations in the corpus
- Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants (2024, background): “In addition, catalase, an enzyme that converts hydrogen peroxide, is usually downregulated in cancer cells (Glorieux et al. 2018; Yun et al. 2015).”
- Mitochondria and Cancer (2016, background): “Promoting mitochondrial ROS production to induce cancer cell death may enhance the activity of chemotherapy (Yun et al., 2015).”
- Vitamin C physiology: the known and the unknown and Goldilocks (2016, positive): “Pharmacologic ascorbate concentrations have antitumor activity in vitro and in animal studies (Chen et al., 2008, Chen et al., 2007) (Parrow et al., 2013, Yun et al., 2015).”
- Targeting Metabolism for Cancer Therapy (2017, background): “Therapeutic interventions that decrease intracellular glutathione levels, such as administration of the oxidized form of vitamin C, dehydroascorbate (DHA), can result in cancer cell death and impaired tumor progression (Yun et al., 2015)”