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

L Jin, D Li, GN Alesi, J Fan, HB Kang, Z Lu, TJ Boggon… - Cancer cell, 2015 - cell.com
L Jin, D Li, GN Alesi, J Fan, HB Kang, Z Lu, TJ Boggon, P Jin, H Yi, ER Wright, D Duong
Cancer cell, 2015cell.com
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 …
Summary
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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