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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • Ascorbic Acid / administration & dosage
  • Ascorbic Acid / pharmacology
  • Ascorbic Acid / therapeutic use*
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Dehydroascorbic Acid / metabolism
  • Female
  • Glucose Transporter Type 1 / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
  • Glycolysis / drug effects
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Mice, Nude
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Reactive Oxygen Species / metabolism
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics*

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • Glucose Transporter Type 1
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • SLC2A1 protein, human
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Ascorbic Acid
  • Dehydroascorbic Acid