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. Bernstein; Ruben D. Carrasco; Daniel P. Cahill; John M. Asara; Christian M. Metallo; Neela H. Yennawar; Matthew G. Vander Heiden; William G. Kaelin

doi:10.1016/j.cell.2018.08.038

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 journal › Article › peer-review

208 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 language	English (US)
Pages (from-to)	101-116.e25
Journal	Cell
Volume	175
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2018.08.038
State	Published - Sep 20 2018
Externally published	Yes

Keywords

BCAT1
BCAT2
IDH1
IDH2
glutaminase
glutathione
radiation
synthetic lethality

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2018.08.038

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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

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, NH, 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

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title = "Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma",

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

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doi = "10.1016/j.cell.2018.08.038",

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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 H.

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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KW - BCAT2

KW - IDH1

KW - IDH2

KW - glutaminase

KW - glutathione

KW - radiation

KW - synthetic lethality

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SN - 0092-8674

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SP - 101-116.e25

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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