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

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

doi:10.1016/j.ccell.2014.12.006

Cited by 309 publications

(302 citation statements)

References 36 publications

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“…Studies have shown that glutamate dehydrogenase plays a key role in regulating redox homeostasis through the activation of GSH-Px [49]. In our study we found that STZ treatment significantly decreased the activity of GDH and increased ROS production, which might have activated the ROS scavenger enzyme, GSH-Px, to regulate the redox homeostasis.…”

Section: Discussionsupporting

confidence: 51%

Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Alnahdi¹,

John²,

Raza³

2018

Cell Physiol Biochem

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Background/Aims: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells. Methods: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. Results: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. Conclusion: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic β-cells against STZ-induced cytotoxicity.

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Section: Discussionsupporting

confidence: 51%

Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Alnahdi¹,

John²,

Raza³

2018

Cell Physiol Biochem

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“…Although NQO1 knockdown potentiated anoikis in non-small cell cancer cells (33), manipulation of the levels of NCF2/p67PHOX, ALOX15, FAT4 and NQO1 produced no significant change in ROS in our cells (data not shown). GRHL2 also down-regulated Glutamate Dehydrogenase 1 (GDH1 or GLUD1), an enzyme implicated in the suppression of ROS (27). By western blotting, we found that GLUD1 protein was upregulated in MSP cells relative to HMLE cells, and downregulated in MSP by GRHL2 expression, in agreement with our RNA-seq data (figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…Following deamination of glutamine to produce glutamate, glutamate dehydrogenase-1 (GLUD1 or GDH1) generates the Krebs cycle intermediate α-ketoglutarate (α-KG), which is converted by the Krebs cycle to fumarate, an important cofactor for glutathione peroxidase enzymes. Accordingly, α-KG is an important protective factor against oxidative stress, and GLUD1 is over-expressed in breast and lung carcinomas (26, 27). …”

Section: Introductionmentioning

confidence: 99%

Grainyhead-like 2 Reverses the Metabolic Changes Induced by the Oncogenic Epithelial–Mesenchymal Transition: Effects on Anoikis

Farris

Pifer

Zheng

et al. 2016

Molecular Cancer Research

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Resistance to anoikis is a pre-requisite for tumor metastasis. The epithelial-to-mesenchymal transition (EMT) allows tumor cells to evade anoikis. The wound healing regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses/reverses EMT, accompanied by suppression of the cancer stem cell (CSC) phenotype and by re-sensitization to anoikis. Here, the effects of GRHL2 upon intracellular metabolism in the context of reversion of the EMT/CSC phenotype, with a view toward understanding how these effects promote anoikis sensitivity were investigated. EMT enhanced mitochondrial oxidative metabolism. While this was accompanied by higher accumulation of superoxide, the overall level of Reactive Oxygen Species (ROS) declined, due to decreased hydrogen peroxide. Glutamate Dehydrogenase 1 (GLUD1) expression increased in EMT, and this increase, via the product α-ketoglutarate (α-KG), was important for suppressing hydrogen peroxide and protecting against anoikis. GRHL2 suppressed GLUD1 gene expression, decreased α-KG, increased ROS and sensitized cells to anoikis. Implications These results demonstrate a mechanistic role for GRHL2 in promoting anoikis through metabolic alterations.

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“…GDH1 is upregulated in human cancers and important for redox homeostasis by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate, which subsequently activates glutathione peroxidase 1, i.e., the antioxidant system. Targeting GDH1 by a small molecule inhibitor, the purpurin analog R162, resulted in an imbalanced redox homeostasis, which led to suppress tumor growth [193] . As described above, the common characteristics of glycolytic inhibitors were to increase ROS levels in cancer cells.…”

Section: Therapeutic Implications Of Targeting the Metabolic Interactmentioning

confidence: 99%

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Lee¹

2015

WJBC

124

115

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Aerobic glycolysis, i.e. , the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e. , the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.

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

Cited by 309 publications

References 36 publications

Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Grainyhead-like 2 Reverses the Metabolic Changes Induced by the Oncogenic Epithelial–Mesenchymal Transition: Effects on Anoikis

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

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