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

Jihye Yun, Edouard Mullarky, Changyuan Lu, Kaitlyn N. Bosch, Adam Kavalier, Keith Rivera, Jatin Roper, Iok In Christine Chio, Eugenia G. Giannopoulou, Carlo Rago, Ashlesha Muley, John M. Asara, Jihye Paik, Olivier Elemento, Zhengming Chen, Darryl J. Pappin, Lukas E. Dow, Nickolas Papadopoulos, Steven S. Gross, Lewis C. Cantley

Research output: Contribution to journalArticlepeer-review

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 BRAFmutations 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.

Original languageEnglish (US)
Pages (from-to)1391-1396
Number of pages6
JournalScience
Volume350
Issue number6266
DOIs
StatePublished - Dec 11 2015

ASJC Scopus subject areas

  • General

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