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Cancer Cell. 2015 Feb 9;27(2):257-70. doi: 10.1016/j.ccell.2014.12.006.

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

Author information

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.

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.

PMID:
25670081
PMCID:
PMC4325424
DOI:
10.1016/j.ccell.2014.12.006
[Indexed for MEDLINE]
Free PMC Article

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