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 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.
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Jihye
authors.initials: J
authors.lastname: Yun
authors.affiliation: 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.
authors.forename: Edouard
authors.initials: E
authors.lastname: Mullarky
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Lu
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kaitlyn N
authors.initials: KN
authors.lastname: Bosch
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Kavalier
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Rivera
authors.affiliation: Molecular Oncology Research Institute and Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Iok In Christine
authors.initials: II
authors.lastname: Chio
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Eugenia G
authors.initials: EG
authors.lastname: Giannopoulou
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rago
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ashlesha
authors.initials: A
authors.lastname: Muley
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Jihye
authors.initials: J
authors.lastname: Paik
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Pappin
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Dow
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. lcantley@med.cornell.edu.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D003683:Dehydroascorbic Acid / Q000378:metabolism; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D051272:Glucose Transporter Type 1; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; C495677:SLC2A1 protein, human; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid