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Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

2015; Cell Press; Volume: 27; Issue: 2 Linguagem: Inglês

10.1016/j.ccell.2014.12.006

1878-3686

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

Metabolomics and Mass Spectrometry Studies

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.