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

Lingtao Jin; Dan Li; Gina N Alesi; Jun Fan; Hee-Bum Kang; Zhou Lu; Titus J Boggon; Peng Jin; Hong Yi; Elizabeth R Wright; Duc Duong; Nicholas T Seyfried; Robert Egnatchik; Ralph J DeBerardinis; Kelly R Magliocca; Chuan He; Martha L Arellano; Hanna J Khoury; Dong M Shin; Fadlo R Khuri; Sumin Kang

doi:10.1016/j.ccell.2014.12.006

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.

Authors

Lingtao Jin¹, Dan Li¹, Gina N Alesi¹, Jun Fan¹, Hee-Bum Kang¹, Zhou Lu², Titus J Boggon³, Peng Jin⁴, Hong Yi⁵, Elizabeth R Wright⁶, Duc Duong⁷, Nicholas T Seyfried⁷, Robert Egnatchik⁸, Ralph J DeBerardinis⁸, Kelly R Magliocca⁹, Chuan He², Martha L Arellano¹, Hanna J Khoury¹, Dong M Shin¹, Fadlo R Khuri¹, Sumin Kang¹⁰

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].

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.

Publication types

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

MeSH terms

Antioxidants / metabolism
Carcinogenesis
Fumarates / metabolism
Gene Expression Regulation, Neoplastic
Glutamate Dehydrogenase / antagonists & inhibitors
Glutamate Dehydrogenase / biosynthesis*
Glutamate Dehydrogenase / genetics
Glutathione / metabolism*
Glutathione Peroxidase / biosynthesis*
Glutathione Peroxidase / genetics
Glutathione Peroxidase GPX1
Humans
Ketoglutaric Acids / metabolism
Leukemia / enzymology
Leukemia / genetics*
Leukemia / pathology
Mitochondria / enzymology*
Mitochondria / pathology
Oxidation-Reduction
Primary Cell Culture
Reactive Oxygen Species / metabolism
Signal Transduction / genetics

Substances

Antioxidants
Fumarates
Ketoglutaric Acids
Reactive Oxygen Species
Glutathione Peroxidase
Glutamate Dehydrogenase
GLUD1 protein, human
Glutathione
Glutathione Peroxidase GPX1
GPX1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding