Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, II, 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. (December 2015) Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science, 350 (6266). pp. 1391-1396. ISSN 1095-9203 (Electronic)0036-8075 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/26541605
DOI: 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 report that cultured 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, ROS accumulates and inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibiting 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 impaired 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > BRAF
diseases & disorders > cancer > cancer types > colon cancer
diseases & disorders > cancer > cancer types > colon cancer

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > KRAS
bioinformatics > genomics and proteomics > small molecules > Vitamin C
CSHL Authors:
Communities: CSHL labs > Pappin lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 11 December 2015
Date Deposited: 13 Nov 2015 17:56
Last Modified: 05 Mar 2018 20:58
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31982

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving