2. Academic Validation
  3. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth

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

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: smkang@emory.edu.
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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