Vitamin C Selectively Kills KRAS and BRAF Mutant Colorectal Cancer Cells by Targeting GAPDH

Overview

Journal Science

Specialty Science

Date 2015 Nov 7

PMID 26541605

Citations 427

Authors

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

Affiliations

Soon will be listed here.

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.

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