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

Samuel K. McBrayer, Jared R. Mayers, Gabriel J. DiNatale, Diana D. Shi, Januka Khanal, Abhishek A. Chakraborty, Kristopher A. Sarosiek, Kimberly J. Briggs, Alissa K. Robbins, Tomasz Sewastianik, Sarah J. Shareef, Benjamin A. Olenchock, Seth J. Parker, Kensuke Tateishi, Jessica B. Spinelli, Mirazul Islam, Marcia C. Haigis, Ryan E. Looper, Keith L. Ligon, Bradley E. BernsteinRuben D. Carrasco, Daniel P. Cahill, John M. Asara, Christian M. Metallo, Neela H. Yennawar, Matthew G. Vander Heiden, William G. Kaelin

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)101-116.e25
JournalCell
Volume175
Issue number1
DOIs
StatePublished - Sep 20 2018
Externally publishedYes

Keywords

  • BCAT1
  • BCAT2
  • glutaminase
  • glutathione
  • IDH1
  • IDH2
  • radiation
  • synthetic lethality

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    McBrayer, S. K., Mayers, J. R., DiNatale, G. J., Shi, D. D., Khanal, J., Chakraborty, A. A., Sarosiek, K. A., Briggs, K. J., Robbins, A. K., Sewastianik, T., Shareef, S. J., Olenchock, B. A., Parker, S. J., Tateishi, K., Spinelli, J. B., Islam, M., Haigis, M. C., Looper, R. E., Ligon, K. L., ... Kaelin, W. G. (2018). Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell, 175(1), 101-116.e25. https://doi.org/10.1016/j.cell.2018.08.038