Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth

  • Cancer Cell. 2015 Feb 9;27(2):257-70. doi: 10.1016/j.ccell.2014.12.006.
Lingtao Jin  1 ,  Dan Li  1 ,  Gina N Alesi  1 ,  Jun Fan  1 ,  Hee-Bum Kang  1 ,  Zhou Lu  2 ,  Titus J Boggon  3 ,  Peng Jin  4 ,  Hong Yi  5 ,  Elizabeth R Wright  6 ,  Duc Duong  7 ,  Nicholas T Seyfried  7 ,  Robert Egnatchik  8 ,  Ralph J DeBerardinis  8 ,  Kelly R Magliocca  9 ,  Chuan He  2 ,  Martha L Arellano  1 ,  Hanna J Khoury  1 ,  Dong M Shin  1 ,  Fadlo R Khuri  1 ,  Sumin Kang  10
Affiliations
  • 1. Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 2. Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
  • 3. Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
  • 4. Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
  • 5. Robert P. Apkarian Integrated Electron Microscopy Core, Emory University, Atlanta, GA 30322, USA.
  • 6. Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 7. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 8. UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 9. Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 10. Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: [email protected].
PMID: 25670081 DOI: 10.1016/j.ccell.2014.12.006
Abstract

How mitochondrial glutaminolysis contributes to redox homeostasis in Cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in Cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a Reactive Oxygen Species scavenging enzyme Glutathione Peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated Cancer cell proliferation and tumor growth.

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