Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells

Lee, Hae Ahm; Chu, Ki Back; Moon, Eun Kyung; Quan, Fu‐Shi

doi:10.3390/antiox10101503

Cited by 5 publications

(3 citation statements)

References 40 publications

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“…Loss of GPx1 induces ER stress ( Geraghty et al, 2016 ; Gansemer et al, 2020 ), and its inhibition makes disulfide-bonded ER client proteins more sensitive to reduction ( Gansemer et al, 2020 ). Similarly, GPx8 suppression was recently shown to enhance ER stress in the liver ( Lee et al, 2021 ). That these manipulations cause ER stress—or, more specifically, induce the UPR—and alter the ER redox environment implies that they do so by affecting the folding, maturation, and secretion of proteins transiting through the ER, but such an effect has not yet been directly demonstrated.…”

Section: Pathways Linking Reduced Nicotinamide Adenine Dinucleotide P...mentioning

confidence: 86%

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Gansemer

Rutkowski

2022

Front. Mol. Biosci.

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The endoplasmic reticulum (ER) lumen is highly oxidizing compared to other subcellular compartments, and maintaining the appropriate levels of oxidizing and reducing equivalents is essential to ER function. Both protein oxidation itself and other essential ER processes, such as the degradation of misfolded proteins and the sequestration of cellular calcium, are tuned to the ER redox state. Simultaneously, nutrients are oxidized in the cytosol and mitochondria to power ATP generation, reductive biosynthesis, and defense against reactive oxygen species. These parallel needs for protein oxidation in the ER and nutrient oxidation in the cytosol and mitochondria raise the possibility that the two processes compete for electron acceptors, even though they occur in separate cellular compartments. A key molecule central to both processes is NADPH, which is produced by reduction of NADP+ during nutrient catabolism and which in turn drives the reduction of components such as glutathione and thioredoxin that influence the redox potential in the ER lumen. For this reason, NADPH might serve as a mediator linking metabolic activity to ER homeostasis and stress, and represent a novel form of mitochondria-to-ER communication. In this review, we discuss oxidative protein folding in the ER, NADPH generation by the major pathways that mediate it, and ER-localized systems that can link the two processes to connect ER function to metabolic activity.

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Section: Pathways Linking Reduced Nicotinamide Adenine Dinucleotide P...mentioning

confidence: 86%

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Gansemer

Rutkowski

2022

Front. Mol. Biosci.

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“…GPX7 may improve non-alcoholic steatohepatitis by regulating oxidative stress levels (Wei et al, 2012). GPX8 can inhibit the oxidative stress response of hepatocellular carcinoma cells (Lee et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Research progress of glutathione peroxidase family (GPX) in redoxidation

et al. 2023

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Maintaining the balance of a cell’s redox function is key to determining cell fate. In the critical redox system of mammalian cells, glutathione peroxidase (GPX) is the most prominent family of proteins with a multifaceted function that affects almost all cellular processes. A total of eight members of the GPX family are currently found, namely GPX1-GPX8. They have long been used as antioxidant enzymes to play an important role in combating oxidative stress and maintaining redox balance. However, each member of the GPX family has a different mechanism of action and site of action in maintaining redox balance. GPX1-4 and GPX6 use selenocysteine as the active center to catalyze the reduction of H2O2 or organic hydroperoxides to water or corresponding alcohols, thereby reducing their toxicity and maintaining redox balance. In addition to reducing H2O2 and small molecule hydroperoxides, GPX4 is also capable of reducing complex lipid compounds. It is the only enzyme in the GPX family that directly reduces and destroys lipid hydroperoxides. The active sites of GPX5 and GPX7-GPX8 do not contain selenium cysteine (Secys), but instead, have cysteine residues (Cys) as their active sites. GPX5 is mainly expressed in epididymal tissue and plays a role in protecting sperm from oxidative stress. Both enzymes, GPX7 and GPX8, are located in the endoplasmic reticulum and are necessary enzymes involved in the oxidative folding of endoplasmic reticulum proteins, and GPX8 also plays an important role in the regulation of Ca2+ in the endoplasmic reticulum. With an in-depth understanding of the role of the GPX family members in health and disease development, redox balance has become the functional core of GPX family, in order to further clarify the expression and regulatory mechanism of each member in the redox process, we reviewed GPX family members separately.

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“…Elevated GPX8 activated Wnt signalling pathway to promote the proliferation, migration, and invasion of gastric cancer cells [ 14 ]. Histone deacetylase inhibitors inhibited the expression of GPX8, which makes hepatocellular carcinoma sensitive to ER stress and apoptosis through oxidative stress [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

GPX8 deficiency–induced oxidative stress reprogrammed m6A epitranscriptome of oral cancer cells

et al. 2023

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Glutathione peroxidase 8 (GPX8) is a key regulator of redox homoeostasis. Whether its antioxidant activity participates in the regulation of m 6 A modification is a crucial issue, which has important application value in cancer treatment. In this study, MeRIP-seq was used to explore the characteristics of transcriptome-wide m 6 A modification in GPX8-deficient oral cancer cells. Oxidative stress caused by the lack of GPX8 resulted in 1,279 hyper- and 2,287 hypo-methylated m 6 A peaks and 2,036 differentially expressed genes in GPX8-KO cells. Twenty-eight differentially expressed genes were related to the cell response to oxidative stress, and half of them changed their m 6 A modification. In GPX8-KO cells, m 6 A regulators IGF2BP2 and IGF2BP3 were upregulated, while FTO, RBM15, VIRMA, ZC3H13, and YTHDC2 were downregulated. After H 2 O 2 treatment, the expression changes of RBM15, IGF2BP2, and IGF2BP3 were further enhanced. These data indicated that GPX8-mediated redox homoeostasis regulated m 6 A modification, thereby affecting the expression and function of downstream genes. This study highlights the possible significance of GPX8 and the corresponding m 6 A regulatory or regulated genes as novel targets for antioxidant intervention in cancer therapy.

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Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells

Cited by 5 publications

References 40 publications

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Research progress of glutathione peroxidase family (GPX) in redoxidation

GPX8 deficiency–induced oxidative stress reprogrammed m6A epitranscriptome of oral cancer cells

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