Inactivation of an enzyme needed to metabolize glucose by Vitamic C deprives tumor cells of energy
Reporter: Aviva Lev-Ari, PhD, RN
Vitamin C did kill cultured colon cancer cells with BRAF or KRAS mutations by raising free radical levels, which in turn inactivate an enzyme needed to metabolize glucose, depriving the cells of energy.
Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
- Jihye Yun1,
- Edouard Mullarky1,2,
- 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. Cantley1,†
+ Author Affiliations
- ↵†Corresponding author. E-mail: lcantley@med.cornell.edu
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↵* Present address: Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn, NY 11201, USA, and Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA.
Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells
- Jihye Yun1,
- Carlo Rago1,
- Ian Cheong1,
- Ray Pagliarini1,*,
- Philipp Angenendt1,
- Harith Rajagopalan1,†,
- Kerstin Schmidt1,
- James K. V. Willson2,
- Sandy Markowitz3,
- Shibin Zhou1,
- Luis A. Diaz Jr1,
- Victor E. Velculescu1,
- Christoph Lengauer1,‡,
- Kenneth W. Kinzler1,
- Bert Vogelstein1,§,
- Nickolas Papadopoulos1
+ Author Affiliations
- ↵§To whom correspondence should be addressed. E-mail: vogelbe@jhmi.edu
DOI: 10.1126/science.1174229
A few years ago, Jihye Yun, then a graduate student at Johns Hopkins University in Baltimore, Maryland, found that colon cancer cells whose growth is driven by mutations in the gene KRAS or a less commonly mutated gene,BRAF, make unusually large amounts of a protein that transports glucose across the cell membrane. The transporter, GLUT1, supplies the cells with the high levels of glucose they need to survive. GLUT1 also transports the oxidized form of vitamin C, dehydroascorbic acid (DHA), into the cell, bad news for cancer cells, because Yun found that DHA can deplete a cell’s supply of a chemical that sops up free radicals. Because free radicals can harm a cell in various ways, the finding suggested “a vulnerability” if the cells were flooded with DHA, says Lewis Cantley at Weill Cornell Medicine in New York City, where Yun is now a postdoc.
Cantley’s lab and collaborators found that large doses of vitamin C did indeed kill cultured colon cancer cells with BRAF or KRAS mutations by raising free radical levels, which in turn inactivate an enzyme needed to metabolize glucose, depriving the cells of energy. Then they gave daily high dose injections—equivalent to a person eating 300 oranges—to mice engineered to develop KRAS-driven colon tumors. The mice developed fewer and smaller colon tumors compared with control mice.
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