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 H.
AU - Vander Heiden, Matthew G.
AU - Kaelin, William G.
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
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.
UR - https://www.scopus.com/pages/publications/85054574107
UR - https://www.scopus.com/inward/citedby.url?scp=85054574107&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.08.038
DO - 10.1016/j.cell.2018.08.038
M3 - Article
C2 - 30220459
AN - SCOPUS:85054574107
SN - 0092-8674
VL - 175
SP - 101-116.e25
JO - Cell
JF - Cell
IS - 1
ER -