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 Jr

doi:10.1016/j.cell.2018.08.038

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

Cell. 2018 Sep 20;175(1):101-116.e25. doi: 10.1016/j.cell.2018.08.038. Epub 2018 Sep 13.

Authors

Samuel K McBrayer¹, Jared R Mayers², Gabriel J DiNatale¹, Diana D Shi¹, Januka Khanal¹, Abhishek A Chakraborty¹, Kristopher A Sarosiek³, Kimberly J Briggs¹, Alissa K Robbins¹, Tomasz Sewastianik⁴, Sarah J Shareef⁵, Benjamin A Olenchock⁶, Seth J Parker⁷, Kensuke Tateishi⁸, Jessica B Spinelli⁹, Mirazul Islam¹⁰, Marcia C Haigis¹¹, Ryan E Looper¹², Keith L Ligon¹³, Bradley E Bernstein⁵, Ruben D Carrasco¹⁴, Daniel P Cahill¹⁵, John M Asara¹⁶, Christian M Metallo⁷, Neela H Yennawar¹⁷, Matthew G Vander Heiden¹⁸, William G Kaelin Jr¹⁹

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ John B. Little Center for Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁴ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
⁵ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁸ Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Yokohama City University, Yokohama, Kanagawa 2360004, Japan.
⁹ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹¹ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Children's Hospital Boston, Boston, MA 02115, USA.
¹⁴ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁵ Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
¹⁷ Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.

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.

Keywords: BCAT1; BCAT2; IDH1; IDH2; glutaminase; glutathione; radiation; synthetic lethality.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Glioma / metabolism*
Glioma / physiopathology
Glutamic Acid / biosynthesis*
Glutamic Acid / drug effects
Glutarates / metabolism
Glutarates / pharmacology
Homeostasis / drug effects
Humans
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / physiology
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / physiology
Mutation
Oxidation-Reduction / drug effects
Pregnancy Proteins / genetics
Pregnancy Proteins / physiology
Transaminases / antagonists & inhibitors
Transaminases / genetics
Transaminases / physiology*

Substances

Glutarates
Minor Histocompatibility Antigens
Pregnancy Proteins
alpha-hydroxyglutarate
Glutamic Acid
Isocitrate Dehydrogenase
IDH1 protein, human
BCAT1 protein, human
Transaminases
BCAT2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding