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 Yennawar, Matthew G. Vander Heiden, William G. Kaelin

Research output: Contribution to journalArticle

14 Citations (Scopus)

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

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Glutaminase
Biosynthesis
Transaminases
Glioma
Oxidation-Reduction
Glutamic Acid
Homeostasis
Bystander Effect
Radiation
Dioxygenases
Mutation
Oxidative stress
Radiation Tolerance
Glioblastoma
Glutathione
Tumors
Oxidative Stress
alpha-hydroxyglutarate
Enzymes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

McBrayer, S. K., Mayers, J. R., DiNatale, G. J., Shi, D. D., Khanal, J., Chakraborty, A. A., ... 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
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 ; Vander Heiden, Matthew G. ; Kaelin, William G. / Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. In: Cell. 2018 ; Vol. 175, No. 1. pp. 101-116.e25.
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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.",
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McBrayer, SK, Mayers, JR, DiNatale, GJ, Shi, DD, Khanal, J, Chakraborty, AA, Sarosiek, KA, Briggs, KJ, Robbins, AK, Sewastianik, T, Shareef, SJ, Olenchock, BA, Parker, SJ, Tateishi, K, Spinelli, JB, Islam, M, Haigis, MC, Looper, RE, Ligon, KL, Bernstein, BE, Carrasco, RD, Cahill, DP, Asara, JM, Metallo, CM, Yennawar, N, Vander Heiden, MG & Kaelin, WG 2018, 'Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma', Cell, vol. 175, no. 1, pp. 101-116.e25. https://doi.org/10.1016/j.cell.2018.08.038

Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. / 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; Vander Heiden, Matthew G.; Kaelin, William G.

In: Cell, Vol. 175, No. 1, 20.09.2018, p. 101-116.e25.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma

AU - McBrayer, Samuel K.

AU - Mayers, Jared R.

AU - DiNatale, Gabriel J.

AU - Shi, Diana D.

AU - Khanal, Januka

AU - Chakraborty, Abhishek A.

AU - Sarosiek, Kristopher A.

AU - Briggs, Kimberly J.

AU - Robbins, Alissa K.

AU - Sewastianik, Tomasz

AU - Shareef, Sarah J.

AU - Olenchock, Benjamin A.

AU - Parker, Seth J.

AU - Tateishi, Kensuke

AU - Spinelli, Jessica B.

AU - Islam, Mirazul

AU - Haigis, Marcia C.

AU - Looper, Ryan E.

AU - Ligon, Keith L.

AU - Bernstein, Bradley E.

AU - Carrasco, Ruben D.

AU - Cahill, Daniel P.

AU - Asara, John M.

AU - Metallo, Christian M.

AU - Yennawar, Neela

AU - Vander Heiden, Matthew G.

AU - Kaelin, William G.

PY - 2018/9/20

Y1 - 2018/9/20

N2 - 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.

AB - 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.

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McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA et al. Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell. 2018 Sep 20;175(1):101-116.e25. https://doi.org/10.1016/j.cell.2018.08.038