Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
Top Cited Papers
- 11 December 2015
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 350 (6266), 1391-1396
- https://doi.org/10.1126/science.aaa5004
Abstract
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.Keywords
Funding Information
- 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
This publication has 42 references indexed in Scilit:
- Ascorbic Acid and a Cytostatic Inhibitor of Glycolysis Synergistically Induce Apoptosis in Non-Small Cell Lung Cancer CellsPLOS ONE, 2013
- Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancerCancer Chemotherapy and Pharmacology, 2013
- Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose MetabolismCell, 2012
- A positive/negative ion–switching, targeted mass spectrometry–based metabolomics platform for bodily fluids, cells, and fresh and fixed tissueNature Protocols, 2012
- Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic CancerPLOS ONE, 2012
- Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor CellsScience, 2009
- Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal CancerJournal of Clinical Oncology, 2008
- K-rasMutations and Benefit from Cetuximab in Advanced Colorectal CancerThe New England Journal of Medicine, 2008
- Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stressJournal of Biology, 2007
- Adenomatous Polyposis Coli (APC) Is Required for Normal Development of Skin and ThymusPLoS Genetics, 2006