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Article Publish Status: FREE
Abstract Title:

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

Abstract Source:

Science. 2015 Nov 5. Epub 2015 Nov 5. PMID: 26541605

Abstract Author(s):

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

Article Affiliation:

Jihye Yun

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/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.

Study Type : Animal Study

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Sayer Ji
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