title: Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth.
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.
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Lingtao
authors: L
authors: Jin
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Dan
authors: D
authors: Li
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Gina N
authors: GN
authors: Alesi
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Jun
authors: J
authors: Fan
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Hee-Bum
authors: HB
authors: Kang
authors: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
authors: Zhou
authors: Z
authors: Lu
authors: Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
authors: Titus J
authors: TJ
authors: Boggon
authors: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
authors: Peng
authors: P
authors: Jin
authors: Robert P. Apkarian Integrated Electron Microscopy Core, Emory University, Atlanta, GA 30322, USA.
authors: Hong
authors: H
authors: Yi
authors: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Elizabeth R
authors: ER
authors: Wright
authors: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Duc
authors: D
authors: Duong
authors: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Nicholas T
authors: NT
authors: Seyfried
authors: UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Robert
authors: R
authors: Egnatchik
authors: UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Ralph J
authors: RJ
authors: DeBerardinis
authors: Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Kelly R
authors: KR
authors: Magliocca
authors: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
authors: Chuan
authors: C
authors: He
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Martha L
authors: ML
authors: Arellano
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Hanna J
authors: HJ
authors: Khoury
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Dong M
authors: DM
authors: Shin
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Fadlo R
authors: FR
authors: Khuri
authors: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: smkang@emory.edu.
authors: Sumin
authors: S
authors: Kang
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D063646:Carcinogenesis; D005650:Fumarates / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D007938:Leukemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D005650:Fumarates; D007656:Ketoglutaric Acids; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human; D005978:Glutathione; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human