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; J. 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

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, J. Hanna J Khoury, Dong M. Shin, Fadlo R. KhuriSumin Kang

Research output: Contribution to journal › Article › peer-review

253 Scopus citations

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.

Original language	English (US)
Pages (from-to)	257-270
Number of pages	14
Journal	Cancer Cell
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2014.12.006
State	Published - Feb 9 2015

ASJC Scopus subject areas

Oncology
Cancer Research

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Jin, L., Li, D., Alesi, G. N., Fan, J., Kang, H. B., Lu, Z., Boggon, T. J., Jin, P., Yi, H., Wright, E. R., Duong, D., Seyfried, N. T., Egnatchik, R., DeBerardinis, R. J., Magliocca, K. R., He, C., Arellano, M. L., Khoury, J. H. J., Shin, D. M., ... Kang, S. (2015). Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth. Cancer Cell, 27(2), 257-270. https://doi.org/10.1016/j.ccell.2014.12.006

Jin, L, Li, D, Alesi, GN, Fan, J, Kang, HB, Lu, Z, Boggon, TJ, Jin, P, Yi, H, Wright, ER, Duong, D, Seyfried, NT, Egnatchik, R, DeBerardinis, RJ, Magliocca, KR, He, C, Arellano, ML, Khoury, JHJ, Shin, DM, Khuri, FR & Kang, S 2015, 'Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth', Cancer Cell, vol. 27, no. 2, pp. 257-270. https://doi.org/10.1016/j.ccell.2014.12.006

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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.",

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

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doi = "10.1016/j.ccell.2014.12.006",

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AU - Lu, Zhou

AU - Boggon, Titus J.

AU - Jin, Peng

AU - Yi, Hong

AU - Wright, Elizabeth R.

AU - Duong, Duc

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AU - Khuri, Fadlo R.

AU - Kang, Sumin

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

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