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Science. 2015 Dec 11;350(6266):1391-6. doi: 10.1126/science.aaa5004. Epub 2015 Nov 5.

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

Author information

1
Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
2
Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
5
Molecular Oncology Research Institute and Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA.
6
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
7
Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
8
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
10
Department of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY 10065, USA.
11
Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. lcantley@med.cornell.edu.

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/Kras(G12D) mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.

PMID:
26541605
PMCID:
PMC4778961
DOI:
10.1126/science.aaa5004
[Indexed for MEDLINE]
Free PMC Article

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