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 - Funding Information:
We thank C. Stiles and J. Alberta at Dana-Farber Cancer Institute (DFCI) for help with the stereotactic surgeries; Kaelin and Losman laboratory members for helpful discussions; I. Mellinghoff (MSKCC), S. Weiss (University of Calgary), and R. Pieper (UCSF) for sharing cell lines; Calithera Biosciences for providing and quantifying CB-839; G. Lu (Celgene) for sharing plasmids; M. Yuan (Harvard) for help with LC-MS/MS; M. Treasure (UNC School of Medicine) for help with enzyme activity assays; DFCI Animal Resources Facility for help with mouse work; and Clyde Bango (DFCI) for help with immunohistochemistry (IHC) experiments. This work was supported by a Brain SPORE grant (P50CA165962) from NIH /NCI (to K.L.L., D.P.C., M.G.V.H., and W.G.K.) and a grant from The Koch Institute /DFCI/Harvard Cancer Center Bridge Project (to D.P.C., M.G.V.H., and W.G.K.). This work was also supported by the following NIH grants: 5R35CA210068 (to W.G.K.), 5P01CA120964 and 5P30CA006516 (to J.M.A.), R01CA188652 (to C.M.M.), and F30CA183474 and T32GM007753 (to J.R.M). S.K.M. is supported by an American Cancer Society fellowship ( PF-14-144-01-TBE ) and a Career Enhancement Project award from the DFCI /Harvard Cancer Center Brain SPORE. M.G.V.H. is a Howard Hughes Medical Institute (HHMI) Faculty Scholar and acknowledges support from SU2C . W.G.K. is an HHMI Investigator.
Funding Information:
We thank C. Stiles and J. Alberta at Dana-Farber Cancer Institute (DFCI) for help with the stereotactic surgeries; Kaelin and Losman laboratory members for helpful discussions; I. Mellinghoff (MSKCC), S. Weiss (University of Calgary), and R. Pieper (UCSF) for sharing cell lines; Calithera Biosciences for providing and quantifying CB-839; G. Lu (Celgene) for sharing plasmids; M. Yuan (Harvard) for help with LC-MS/MS; M. Treasure (UNC School of Medicine) for help with enzyme activity assays; DFCI Animal Resources Facility for help with mouse work; and Clyde Bango (DFCI) for help with immunohistochemistry (IHC) experiments. This work was supported by a Brain SPORE grant (P50CA165962) from NIH/NCI (to K.L.L., D.P.C., M.G.V.H., and W.G.K.) and a grant from The Koch Institute/DFCI/Harvard Cancer Center Bridge Project (to D.P.C., M.G.V.H., and W.G.K.). This work was also supported by the following NIH grants: 5R35CA210068 (to W.G.K.), 5P01CA120964 and 5P30CA006516 (to J.M.A.), R01CA188652 (to C.M.M.), and F30CA183474 and T32GM007753 (to J.R.M). S.K.M. is supported by an American Cancer Society fellowship (PF-14-144-01-TBE) and a Career Enhancement Project award from the DFCI/Harvard Cancer Center Brain SPORE. M.G.V.H. is a Howard Hughes Medical Institute (HHMI) Faculty Scholar and acknowledges support from SU2C. W.G.K. is an HHMI Investigator.
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 - http://www.scopus.com/inward/record.url?scp=85054574107&partnerID=8YFLogxK
UR - http://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 -