학술논문
Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
Document Type
Author abstract
Author
Yun, Jihye; Mullarky, Edouard; Lu, Changyuan; Bosch, Kaitlyn N.; Kavalier, Adam; Rivera, Keith; Roper, Jatin; Chio, Iok In Christine; Giannopoulou, Eugenia G.; Rago, Carlo; Muley, Ashlesha; Asara, John M.; Paik, Jihye; Elemento, Olivier; Chen, Zhengming; Pappin, Darryl J.; Dow, Lukas E.; Papadopoulos, Nickolas; Gross, Steven S.; Cantley, Lewis C.
Source
Science. Dec 11, 2015, Vol. 350 Issue 6266, p1391, 6 p.
Subject
Language
English
ISSN
0036-8075
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.sup.G12D] mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations. 10.1126/science.aaa5004