Publication Date:
2015-11-07
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778961/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778961/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- KL2 TR000458/TR/NCATS NIH HHS/ -- P01 CA117969/CA/NCI NIH HHS/ -- P01 CA117969-09/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01 CA120964-07/CA/NCI NIH HHS/ -- S10 RR022615/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Dec 11;350(6266):1391-6. doi: 10.1126/science.aaa5004. Epub 2015 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. ; 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. ; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. ; Molecular Oncology Research Institute and Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA. ; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA. ; Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. ; Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. ; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. ; Department of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY 10065, USA. ; Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. lcantley@med.cornell.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26541605" target="_blank"〉PubMed〈/a〉
Keywords:
Adenomatous Polyposis Coli Protein/genetics
;
Animals
;
Ascorbic Acid/administration & dosage/pharmacology/*therapeutic use
;
Cell Line, Tumor
;
Colorectal Neoplasms/*drug therapy/*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
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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