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

Science. 2015 Dec 11;350(6266):1391-6. doi: 10.1126/science.aaa5004. Epub 2015 Nov 5.

Authors

Jihye Yun¹, Edouard Mullarky², Changyuan Lu³, Kaitlyn N Bosch¹, Adam Kavalier³, Keith Rivera⁴, Jatin Roper⁵, Iok In Christine Chio⁴, Eugenia G Giannopoulou⁶, Carlo Rago⁷, Ashlesha Muley¹, John M Asara⁸, Jihye Paik⁹, Olivier Elemento⁶, Zhengming Chen¹⁰, Darryl J Pappin⁴, Lukas E Dow¹, Nickolas Papadopoulos⁷, Steven S Gross³, Lewis C Cantley¹¹

Affiliations

¹ Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
² Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
⁴ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
⁵ Molecular Oncology Research Institute and Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA.
⁶ Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
⁷ Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
⁸ Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁹ Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
¹⁰ Department of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY 10065, USA.
¹¹ Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenomatous Polyposis Coli Protein / genetics
Animals
Ascorbic Acid / administration & dosage
Ascorbic Acid / pharmacology
Ascorbic Acid / therapeutic use*
Cell Line, Tumor
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / genetics*
Dehydroascorbic Acid / metabolism
Female
Glucose Transporter Type 1 / metabolism
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
Glycolysis / drug effects
Humans
Mice
Mice, Mutant Strains
Mice, Nude
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins B-raf / genetics*
Proto-Oncogene Proteins p21(ras) / genetics
Reactive Oxygen Species / metabolism
Xenograft Model Antitumor Assays
ras Proteins / genetics*

Substances

APC protein, human
Adenomatous Polyposis Coli Protein
Glucose Transporter Type 1
KRAS protein, human
Proto-Oncogene Proteins
Reactive Oxygen Species
SLC2A1 protein, human
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
BRAF protein, human
Proto-Oncogene Proteins B-raf
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)
ras Proteins
Ascorbic Acid
Dehydroascorbic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding