Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
Open accessAbstract
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
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Therapeutic interventions that decrease intracellular glutathione, such as dehydroascorbate, can result in cancer cell death and impaired tumor progression.
“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)”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Yun et al., 2015
Highly glycolytic RAS-mutant cells are vulnerable to GAPDH inhibition by vitamin C, providing a rationale for testing it in KRAS- or BRAF-mutant colorectal cancer preclinical models.
“Highly glycolytic RAS-mutant cells have been found to be vulnerable to inhibition of the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with Vitamin C, providing a mechanistic rationale for exploring the therapeutic use of this vitamin against KRAS or BRAF mutant colorectal cancer preclinical models 38.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [38]
Within cells, DHA is quickly converted back to ascorbate while consuming GSH and NADPH.
“Inside the cell, DHA is rapidly reduced back to ascorbate at the expense of GSH and NADPH47,49.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
High-dose ascorbate can attack the weaknesses of colorectal cancer cells with KRAS or BRAF mutations.
“we recently showed that high-dose ascorbate can target these vulnerabilities in KRAS or BRAF mutant colorectal cancer (CRC) cells47.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
The active pharmacological agent in ascorbate therapy is DHA.
“our study indicated that DHA is the pharmacologically active agent”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
Cancer cells with high GLUT1, rather than sodium-dependent vitamin C transporters, take up ascorbate only as DHA in culture and in animals.
“cancer cells with high GLUT1 but not sodium-dependent vitamin C transporters exclusively take up ascorbate in the form of DHA both in vitro or in vivo6,8,47,53.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
ROS turns on PARP, lowering NAD+ and further blocking GAPDH.
“ROS leads to activation of poly(ADP-ribose) polymerase (PARP), which in turn leads to depletion of NAD+ (a key cofactor of GAPDH), thereby further inhibiting GAPDH47”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
Higher ROS inactivates the glycolytic enzyme GAPDH by oxidizing an active-site cysteine.
“The elevated ROS, in turn, inactivates a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), by oxidizing a cysteine residue in the active site.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
Administered ascorbate becomes DHA, which resembles glucose and is efficiently imported through GLUT1 in KRAS or BRAF mutant cells.
“When ascorbate is administered, it is oxidized to DHA. Owing to its structural similarity to glucose, DHA is efficiently taken up via GLUT1 in KRAS or BRAF mutant cells47,48”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
That conversion lowers intracellular antioxidants and raises endogenous ROS.
“This reduction depletes intracellular antioxidants and increases endogenous levels of ROS47,50.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In Apc−/−;KrasG12D/+ mice, daily intraperitoneal ascorbate (4 g kg−1) slowed tumour growth, but it did not affect tumours in Apc−/− mice.
“daily intraperitoneal injection of ascorbate (4 g kg−1) inhibited tumour growth in Apc−/−;KrasG12D/+ mutant mice whereas it did not affect tumour growth in Apc−/− mice47.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
Blocking GAPDH in highly glycolytic KRAS or BRAF mutant cells causes an energy crisis and death that wild-type cells do not suffer.
“Inhibiting GAPDH in highly glycolytic KRAS or BRAF mutant cells ultimately leads to an ‘energy crisis’ and cell death not seen in their wild-type counterparts47.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
In colorectal cancer cells with KRAS or BRAF mutations, GLUT1-mediated uptake of dehydroascorbic acid followed by its conversion to ascorbate lowers essential antioxidants, causing cell death.
“This study demonstrates that uptake of DHA by GLUT1, and its subsequent reduction to ascorbate, depletes essential antioxidants to induce cell death in KRAS or BRAF mutant CRC cells.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [47]
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- Authors
- Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S., & Cantley, L. C.
- Affiliations
- Weill Cornell Medicine (US)
- Harvard University (US)
- Cold Spring Harbor Laboratory (US)
- Tufts Medical Center (US)
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
- Howard Hughes Medical Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Cantley, Lewis C.
- ORCID
- Venue
- Science
- Published
- 2015-12-11
- Volume
- 350
- Issue
- 6266
- Pages
- 1391-1396
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4778961
- OpenAlex
- W2144542772
- Cited by
- 913
- References
- 40
- Citations by year
- 2026: 49 · 2025: 83 · 2024: 71 · 2023: 73 · 2022: 106 · 2021: 111 · 2020: 110 · 2019: 92 · 2018: 88 · 2017: 85 · 2016: 43 · 2015: 2
- FWCI
- 69.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P01 CA120964)
- U.S. Department of Defense
- National Cancer Institute (P01 CA120964-07, P01 CA117969-09)
- Damon Runyon Cancer Research Foundation
- KL2 Career Development
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- vitamin C, dehydroascorbic acid, KRAS mutation, BRAF mutation, colorectal cancer, glyceraldehyde-3-phosphate dehydrogenase, GLUT1 glucose transporter, glutathione depletion, reactive oxygen species, oxidative stress, glycolysis, cell death, targeted therapy
- MeSH terms
- Animals, Ascorbic Acid, Dehydroascorbic Acid, Female, Glycolysis, Humans, Mice, Mutant Strains, Mice, Nude, Proto-Oncogene Proteins, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Reactive Oxygen Species, ras Proteins, Xenograft Model Antitumor Assays, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Adenomatous Polyposis Coli Protein, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Glucose Transporter Type 1, Mice
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