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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 H; Vander Heiden, Matthew G; Kaelin, William G.
Afiliação
  • McBrayer SK; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Mayers JR; 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.
  • DiNatale GJ; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Shi DD; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Khanal J; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Chakraborty AA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Sarosiek KA; John B. Little Center for Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Briggs KJ; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Robbins AK; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Sewastianik T; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
  • Shareef SJ; 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.
  • Olenchock BA; 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
  • Parker SJ; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
  • Tateishi K; 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.
  • Spinelli JB; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Islam M; 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.
  • Haigis MC; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Looper RE; Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
  • Ligon KL; 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 Ho
  • Bernstein BE; 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.
  • Carrasco RD; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Cahill DP; Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Asara JM; 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.
  • Metallo CM; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
  • Yennawar NH; Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
  • Vander Heiden MG; 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
  • Kaelin WG; 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.
Cell ; 175(1): 101-116.e25, 2018 09 20.
Article em En | MEDLINE | ID: mdl-30220459
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.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Ácido Glutâmico / Glioma / Transaminases Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Outros_tipos Base de dados: MEDLINE Assunto principal: Ácido Glutâmico / Glioma / Transaminases Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos