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

doi:10.1126/science.aaa5004

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

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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 language	English (US)
Pages (from-to)	1391-1396
Number of pages	6
Journal	Science
Volume	350
Issue number	6266
DOIs	https://doi.org/10.1126/science.aaa5004
State	Published - Dec 11 2015
Externally published	Yes

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Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S., & Cantley, L. C. (2015). Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science, 350(6266), 1391-1396. https://doi.org/10.1126/science.aaa5004

Yun, J, Mullarky, E, Lu, C, Bosch, KN, Kavalier, A, Rivera, K, Roper, J, Chio, IIC, Giannopoulou, EG, Rago, C, Muley, A, Asara, JM, Paik, J, Elemento, O, Chen, Z, Pappin, DJ, Dow, LE, Papadopoulos, N, Gross, SS & Cantley, LC 2015, 'Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH', Science, vol. 350, no. 6266, pp. 1391-1396. https://doi.org/10.1126/science.aaa5004

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title = "Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH",

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.",

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

year = "2015",

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doi = "10.1126/science.aaa5004",

language = "English (US)",

volume = "350",

pages = "1391--1396",

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T1 - Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

AU - Yun, Jihye

AU - Mullarky, Edouard

AU - Lu, Changyuan

AU - Bosch, Kaitlyn N.

AU - Kavalier, Adam

AU - Rivera, Keith

AU - Roper, Jatin

AU - Chio, Iok In Christine

AU - Giannopoulou, Eugenia G.

AU - Rago, Carlo

AU - Muley, Ashlesha

AU - Asara, John M.

AU - Paik, Jihye

AU - Elemento, Olivier

AU - Chen, Zhengming

AU - Pappin, Darryl J.

AU - Dow, Lukas E.

AU - Papadopoulos, Nickolas

AU - Gross, Steven S.

AU - Cantley, Lewis C.

PY - 2015/12/11

Y1 - 2015/12/11

N2 - 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.

AB - 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.

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

Abstract

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