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 journalArticle

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

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Glyceraldehyde-3-Phosphate Dehydrogenases
Ascorbic Acid
Colorectal Neoplasms
Mutation
Facilitative Glucose Transport Proteins
Therapeutic Uses
Glutathione
Reactive Oxygen Species
Oxidative Stress
Cell Death
Growth
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., ... 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

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

In: Science, Vol. 350, No. 6266, 11.12.2015, p. 1391-1396.

Research output: Contribution to journalArticle

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
Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015 Dec 11;350(6266):1391-1396. https://doi.org/10.1126/science.aaa5004
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. / Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. In: Science. 2015 ; Vol. 350, No. 6266. pp. 1391-1396.
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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.",
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AU - Rivera, Keith

AU - Roper, Jatin

AU - Chio, Iok In Christine

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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.

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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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