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Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma

Author(s)
McBrayer, Samuel K.; Mayers, Jared R.; DiNatale, Gabriel J.; Shi, Diana D.; Khanal, Januka; Chakraborty, Abhishek A.; Sarosiek, Kristopher A.; Briggs, Kimberly J.; Robbins, Alissa K.; Sewastianik, Tomasz; Shareef, Sarah J.; Olenchock, Benjamin A.; Parker, Seth J.; Tateishi, Kensuke; Spinelli, Jessica B.; Islam, Mirazul; Haigis, Marcia C.; Looper, Ryan E.; Ligon, Keith L.; Bernstein, Bradley E.; Carrasco, Ruben D.; Cahill, Daniel P.; Asara, John M.; Metallo, Christian M.; Yennawar, Neela H.; Vander Heiden, Matthew G.; Kaelin, William G.; ... Show more Show less
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Abstract
IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas. Gliomas with IDH mutations show increased sensitivity to radiation in concert with glutaminase inhibition, offering a new approach to treating these tumors.
Date issued
2018-09
URI
https://hdl.handle.net/1721.1/125155
Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Journal
Cell
Publisher
Elsevier BV
Citation
McBrayer, Samuel K. et al. "Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma." Cell 175, 1 (September 2018): P101-116.e25 © 2018 Elsevier Inc
Version: Author's final manuscript
ISSN
0092-8674

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