Gene Summary

Gene:GPX1; glutathione peroxidase 1
Aliases: GPXD, GSHPX1
Summary:The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Other studies indicate that H2O2 is also essential for growth-factor mediated signal transduction, mitochondrial function, and maintenance of thiol redox-balance; therefore, by limiting H2O2 accumulation, glutathione peroxidases are also involved in modulating these processes. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is the most abundant, is ubiquitously expressed and localized in the cytoplasm, and whose preferred substrate is hydrogen peroxide. It is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. This gene contains an in-frame GCG trinucleotide repeat in the coding region, and three alleles with 4, 5 or 6 repeats have been found in the human population. The allele with 4 GCG repeats has been significantly associated with breast cancer risk in premenopausal women. Alternatively spliced transcript variants have been found for this gene. Pseudogenes of this locus have been identified on chromosomes X and 21. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glutathione peroxidase 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (48)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • RHOA
  • Single Nucleotide Polymorphism
  • Prostate Cancer
  • Transcription Factors
  • Superoxide Dismutase
  • Selenocysteine
  • Biomarkers, Tumor
  • Hepatocellular Carcinoma
  • TGFB1
  • Oxidative Stress
  • Sunburn
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Polymorphism
  • Messenger RNA
  • Genetic Predisposition
  • beta Carotene
  • Thioredoxin Reductase 2
  • Superoxide Dismutase-1
  • Ursodeoxycholic Acid
  • Survival Rate
  • Risk Factors
  • Odds Ratio
  • Genotype
  • Lung Cancer
  • Breast Cancer
  • Publication Bias
  • Glutathione Peroxidase
  • Subcellular Fractions
  • Stomach Cancer
  • Bladder Cancer
  • Research Design
  • Cancer Gene Expression Regulation
  • Catalase
  • Alleles
  • Chromosome 3
  • Selenium-Binding Proteins
  • Case-Control Studies
  • Antioxidants
  • Mutation
  • rac GTP-Binding Proteins
  • Liver Cancer
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: GPX1 (cancer-related)

Chen B, Shen Z, Wu D, et al.
Glutathione Peroxidase 1 Promotes NSCLC Resistance to Cisplatin via ROS-Induced Activation of PI3K/AKT Pathway.
Biomed Res Int. 2019; 2019:7640547 [PubMed] Free Access to Full Article Related Publications
Purpose: Reactive oxygen species (ROS)-induced cytotoxicity is an important mechanism by which cisplatin kills tumor cells. Glutathione peroxidase family (GPXs) is an important member of antioxidant system which metabolizes intracellular ROS and maintains homeostasis of cells. Altered expressions of GPXs enzymes, especially GPX1, have been described in a variety of human cancers. However, their functional roles in cisplatin-based chemoresistance in human malignancies including non-small cell lung cancer have never been explored.
Methods: A panel of NSCLC cell lines were selected for this study. GPX1 expression was detected using quantitative RT-PCR and Western blot. Cisplatin-induced cell killing was analyzed by CCK8 assay. Intracellular ROS levels were detected by fluorescence-based flow cytometry analysis. In vitro overexpression and knockdown of GPX1 expression were performed using GPX1 expression vector and siRNA approaches. Protein levels of PTEN, NF-
Results: GPX1 expression was upregulated in a subset of NSCLC cell lines resistant to cisplatin treatment. Expression vector-mediated forced overexpression of GPX1 significantly increased cisplatin resistance in NSCLC cell lines, whereas RNA inference-mediated downregulation of GPX1 could restore sensitivity to cisplatin. Overexpression of GPX1 significantly suppressed elevation of intracellular ROS and activation of AKT pathway when NSCLC cell lines were exposed to different concentrations of cisplatin. Activation of the AKT pathway inhibited proapoptotic cascade and subsequently led to cisplatin resistance in NSCLC cells. Inhibition of NF-
Conclusions: Our findings suggested that overexpression of GPX1 is a novel molecular mechanism for cisplatin-based chemoresistance in NSCLC. GPX1 overexpression blocks cisplatin-induced ROS intracellular accumulation, activates PI3K-AKT pathway by increased AKT phosphorylation, and further leads to cisplatin resistance in NSCLC cells. Inhibition of NF-

Mahbouli S, Talvas J, der Vartanian A, et al.
Activation of antioxidant defences of human mammary epithelial cells under leptin depend on neoplastic state.
BMC Cancer. 2018; 18(1):1264 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Obesity is associated with oxidative stress, a major factor in carcinogenesis, and with high leptin concentration. The aim of this study was to determine the effects of leptin on the antioxidant response in three human mammary epithelial cells each presenting a different neoplastic status: healthy human mammary epithelial cells (HMEC), oestrogen-receptor positive MCF-7 cells and triple-negative MDA-MB-231 cells.
METHODS: This in vitro kinetic study characterized the cell antioxidant response after 1, 6 and 24 h in the presence of leptin (10 or 100 ng/ml).The antioxidant response was defined in terms of cell glutathione content, gene expression and catalytic activity of antioxidant enzymes (i.e. glutathione peroxidase 1 (Gpx1), glutathione reductase (GR), glutathione S transferase (GST), heme-oxygenase 1 (HO-1) and cyclooxygenase-2 (COX-2)). Oxidative stress occurrence was assessed by lipid hydro peroxide (HPLIP) and isoprostane concentrations in culture media at 24 h.
RESULTS: At both concentrations used, leptin induced ROS production in all cell models, contributing to various antioxidant responses linked to neoplastic cell status. HMEC developed a highly inducible antioxidant response based on antioxidant enzyme activation and an increase in cell GSH content at 10 ng/ml of leptin. However, at 100 ng/ml of leptin, activation of antioxidant response was lower. Conversely, in tumour cells, MCF-7 and MDA-MB-231, leptin did not induce an efficient antioxidant response, at either concentration, resulting in an increase of lipid peroxidation products.
CONCLUSIONS: Leptin can modulate the oxidative status of mammary epithelial cells differently according to their neoplastic state. These novel results shed light on oxidative status changes in mammary cells in the presence of leptin.

Hughes DJ, Kunická T, Schomburg L, et al.
Expression of Selenoprotein Genes and Association with Selenium Status in Colorectal Adenoma and Colorectal Cancer.
Nutrients. 2018; 10(11) [PubMed] Free Access to Full Article Related Publications
Dietary selenium (Se) intake is essential for synthesizing selenoproteins that are important in countering oxidative and inflammatory processes linked to colorectal carcinogenesis. However, there is limited knowledge on the selenoprotein expression in colorectal adenoma (CRA) and colorectal cancer (CRC) patients, or the interaction with Se status levels. We studied the expression of seventeen Se pathway genes (including fifteen of the twenty-five human selenoproteins) in RNA extracted from disease-normal colorectal tissue pairs, in the discovery phase of sixty-two CRA/CRC patients from Ireland and a validation cohort of a hundred and five CRC patients from the Czech Republic. Differences in transcript levels between the disease and paired control mucosa were assessed by the Mann-Whitney U-test.

Zhang H, Zhao W, Gu D, et al.
Association of Antioxidative Enzymes Polymorphisms with Efficacy of Platin and Fluorouracil-Based Adjuvant Therapy in Gastric Cancer.
Cell Physiol Biochem. 2018; 48(6):2247-2257 [PubMed] Related Publications
BACKGROUND/AIMS: Imbalance of oxidative/antioxidative enzymes in cells is associated with carcinogenesis and cancer cell chemoresistance. The aim of this study was to examine the clinical significance of potentially functional single nucleotides polymorphisms (SNPs) in antioxidative enzymes, GPxs and CAT, in stages II and III gastric cancer patients.
METHODS: A total of 591 gastric cancer patients who had radical gastrectomy were recruited. 207 patients received platinum and fluorouracil-based (PF-based) adjuvant chemotherapy and 384 patients were untreated. GPx1 rs1050450, GPx2 rs4902346, GPx3 rs736775, rs3828599 and CAT rs769218 were genotyped in the DNA samples extracted from paraffin-embedded tumor tissue.
RESULTS: CAT rs769218 was significantly correlated with the overall survival (OS) in the dominant model (P = 0.014). Multivariate analysis revealed that CAT rs769218 GA/AA (HR, 0.715; 95%CI, 0.562-0.910, P = 0.006) was an independent prognostic marker indicating improved survival. After adjustments, GPx3 rs736775 TC/CC was significantly associated with improved OS (HR, 0.621; 95%CI, 0.399-0.965; P=0.034) in patients treated with PF-based adjuvant chemotherapy, and CAT rs769218 GA/AA was significantly associated with improved OS (HR, 0.646; 95% CI, 0.482-0.864; P = 0.003) in the untreated patients. PF-based chemotherapy significantly decreased risk of death for patients carrying GPx3 rs736775 TC/CC and age ≤ 60 years or with diffused type adenocarcinoma compared to surgery alone.
CONCLUSION: our findings suggested CAT rs769218 and GPx3 rs736775 may be considered as prognostic markers in gastric cancer. Patient stratification by GPx3 rs736775 and conventional pathological parameters may provide additional predictive information in treatment decision-making.

Król MB, Galicki M, Grešner P, et al.
The ESR1 and GPX1 gene expression level in human malignant and non-malignant breast tissues.
Acta Biochim Pol. 2018; 65(1):51-57 [PubMed] Related Publications
BACKGROUND: The aim of this study was to establish whether the gene expression of estrogen receptor alpha (encoded by ESR1) correlates with the expression of glutathione peroxidase 1 (encoded by GPX1) in the tumor and adjacent tumor-free breast tissue, and whether this correlation is affected by breast cancer. Such relationships may give further insights into breast cancer pathology with respect to the status of estrogen receptor.
METHODS: We used the quantitative real-time PCR technique to analyze differences in the expression levels of the ESR1 and GPX1 genes in paired malignant and non-malignant tissues from breast cancer patients.
RESULTS: ESR1 and GPX1 expression levels were found to be significantly down-regulated by 14.7% and 7.4% (respectively) in the tumorous breast tissue when compared to the non-malignant one. Down-regulation of these genes was independent of the tumor histopathology classification and clinicopathological factors, while the ESR1 mRNA level was reduced with increasing tumor grade (G1: 103% vs. G2: 85.8% vs. G3: 84.5%; p<0.05). In the non-malignant and malignant breast tissues, the expression levels of ESR1 and GPX1 were significantly correlated with each other (Rs=0.450 and Rs=0.360; respectively).
CONCLUSION: Our data suggest that down-regulation of ESR1 and GPX1 was independent of clinicopathological factors. Down-regulation of ESR1 gene expression was enhanced by the development of the disease. Moreover, GPX1 and ESR1 gene expression was interdependent in the malignant breast tissue and further work is needed to determine the mechanism underlying this relationship.

Habyarimana T, Bakri Y, Mugenzi P, et al.
Association between glutathione peroxidase 1 codon 198 variant and the occurrence of breast cancer in Rwanda.
Mol Genet Genomic Med. 2018; 6(2):268-275 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glutathione peroxidase 1 gene (GPX1) is one of the antioxidant enzyme that remove the reactive oxygen species in a continuous process. Since the identification of a well-characterized functional polymorphism named p.Pro198Leu (rs1050450 C>T) in GPX1 gene, abundant studies have evaluated the association between p.Pro198Leu polymorphism and tumor risk in diverse population. But, the available results related to breast cancer are conflicting and absent in Africa. The present case-control study was planned to assess the presence of GPX1 Pro198Leu polymorphism in Rwanda population to determine whether it is associated with the risk of developing breast cancer.
METHODS: Genomic DNA from peripheral blood leukocytes of 41 patients with breast cancer and 42 healthy controls were enrolled and genotyped GPX1 Pro198Leu polymorphism by PCR amplification and DNA sequencing.
RESULTS: No significant difference in the frequencies of Pro/Pro (49%) and Pro/Leu (51%) genotypes in cancer cases and in controls (50% each) were found. The allelic frequencies of Pro and Leu were 74% versus 26% and 75% versus 25% in breast cancer cases and controls respectively. No association was observed in allele frequencies of Pro and Leu, and familial history. Only an overall association of GPX1 Pro198Leu with grade of cancer (Pro/Leu vs. Pro/Pro: p = .0200) was detected.
CONCLUSION: The result of this study suggested that GPX1 Pro198Leu polymorphism could not be a risk factor for breast cancer in Rwanda. However, large-scale studies on the effect of this polymorphism on the factors disturbing the redox homeostasis are needed for conclusive understanding.

Gardaneh M, Shojaei S, Rahimi Shamabadi A, Akbari P
Breast Cancer Cell Apoptosis is Synergistically Induced by Curcumin, Trastuzumab, and Glutathione Peroxidase-1 but Robustly Inhibited by Glial Cell Line-Derived Neurotrophic Factor.
Nutr Cancer. 2018 Feb-Mar; 70(2):288-296 [PubMed] Related Publications
We hypothesized that synergy between curcumin (CURC), trastuzumab (TZMB), and glutathione peroxidase-1 (GPX-1) accelerates breast cancer (BC) cell apoptosis which is inhibited by glial cell line-derived neurotrophic factor (GDNF). We measured survival of BC cell lines treated or cotreated with CURC and TZMB, and then with GDNF, before measuring expression levels of growth and apoptosis genes. These experiments were also repeated on SKBR3 cells transiently expressing GPX-1. CURC+TZMB cotreatment induced BC cell apoptosis more significantly than single treatment. GDNF highly inhibited CURC+TZMB toxicity and restored survival. Ectopic overexpression of GPX-1 per se induced SKBR3 cell death that was accelerated upon CURC+TZMB cotreatment. This substantial death induction was inhibited by GDNF more robustly than in single-treated cells. All these changes correlated with changes in expression levels of key molecules and were further confirmed by flow cytometry and correlation analysis. Our data indicate apoptotic induction is jointly shaped in BC cells by CURC, TZMB, and GPX-1 which correlates directly with their tripartite synergism and inversely with GDNF progrowth effects. In light of the active presence of GDNF in tumor microenvironment and necessity to overcome drug resistance, our findings can help in designing combined therapeutic strategies with implications for challenging TZMB resistance in BC.

Glei M, Fischer S, Lamberty J, et al.
Chemopreventive Potential of
Anticancer Res. 2018; 38(1):83-93 [PubMed] Related Publications
BACKGROUND/AIM: Due to their unique composition of health-promoting compounds, the consumption of hazelnuts may contribute to the prevention of colon cancer.
MATERIALS AND METHODS: Since hazelnuts are often consumed roasted, the impact of different roasting conditions (RC1=140.6°C/25 min, RC2=155.1°C/20 min and RC3=180.4°C/21 min) on chemopreventive effects of in vitro fermented hazelnuts was analyzed in LT97 colon adenoma cells.
RESULTS: FS (2.5%) of raw and roasted hazelnuts reduced H
CONCLUSION: These results indicate a chemopreventive potential of in vitro fermented hazelnuts which is largely unaffected by the roasting process.

Glei M, Ludwig D, Lamberty J, et al.
Chemopreventive Potential of Raw and Roasted Pistachios Regarding Colon Carcinogenesis.
Nutrients. 2017; 9(12) [PubMed] Free Access to Full Article Related Publications
Pistachios are rich in health-promoting bioactive compounds such as B vitamins, γ-tocopherol, polyphenols and dietary fiber, which could contribute to the reduction of colon cancer risk in terms of chemoprevention (Fischer, S.; Glei, M. Health-Potential of Nuts. Ernaehrungs Umsch. Int. 2013, 60, 206-215.). Since pistachios are often consumed roasted, the present study aims at investigating the influence of different roasting conditions (RC) on potential chemopreventive effects of pistachios in colon adenoma cells such as growth and apoptosis, genotoxic- and anti-genotoxic effects and modulation of gene expression of detoxifying enzymes (

Khan RB, Phulukdaree A, Chuturgoon AA
Fumonisin B
Toxicon. 2018; 141:104-111 [PubMed] Related Publications
Fumonisin B

Caglayan A, Katlan DC, Selçuk Tuncer Z, et al.
Impaired antioxidant enzyme functions with increased lipid peroxidation in epithelial ovarian cancer.
IUBMB Life. 2017; 69(10):802-813 [PubMed] Related Publications
We aimed to identify the possible role of oxidant-antioxidant status in epithelial ovarian cancer (EOC) by measuring (a) antioxidant enzyme (AOE) activities [total superoxide dismutase (SOD

Chaudhary R, Gryder B, Woods WS, et al.
Prosurvival long noncoding RNA
Elife. 2017; 6 [PubMed] Free Access to Full Article Related Publications
Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named

Yeo J, Crawford EL, Zhang X, et al.
A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells.
BMC Cancer. 2017; 17(1):301 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Annual low dose CT (LDCT) screening of individuals at high demographic risk reduces lung cancer mortality by more than 20%. However, subjects selected for screening based on demographic criteria typically have less than a 10% lifetime risk for lung cancer. Thus, there is need for a biomarker that better stratifies subjects for LDCT screening. Toward this goal, we previously reported a lung cancer risk test (LCRT) biomarker comprising 14 genome-maintenance (GM) pathway genes measured in normal bronchial epithelial cells (NBEC) that accurately classified cancer (CA) from non-cancer (NC) subjects. The primary goal of the studies reported here was to optimize the LCRT biomarker for high specificity and ease of clinical implementation.
METHODS: Targeted competitive multiplex PCR amplicon libraries were prepared for next generation sequencing (NGS) analysis of transcript abundance at 68 sites among 33 GM target genes in NBEC specimens collected from a retrospective cohort of 120 subjects, including 61 CA cases and 59 NC controls. Genes were selected for analysis based on contribution to the previously reported LCRT biomarker and/or prior evidence for association with lung cancer risk. Linear discriminant analysis was used to identify the most accurate classifier suitable to stratify subjects for screening.
RESULTS: After cross-validation, a model comprising expression values from 12 genes (CDKN1A, E2F1, ERCC1, ERCC4, ERCC5, GPX1, GSTP1, KEAP1, RB1, TP53, TP63, and XRCC1) and demographic factors age, gender, and pack-years smoking, had Receiver Operator Characteristic area under the curve (ROC AUC) of 0.975 (95% CI: 0.96-0.99). The overall classification accuracy was 93% (95% CI 88%-98%) with sensitivity 93.1%, specificity 92.9%, positive predictive value 93.1% and negative predictive value 93%. The ROC AUC for this classifier was significantly better (p < 0.0001) than the best model comprising demographic features alone.
CONCLUSIONS: The LCRT biomarker reported here displayed high accuracy and ease of implementation on a high throughput, quality-controlled targeted NGS platform. As such, it is optimized for clinical validation in specimens from the ongoing LCRT blinded prospective cohort study. Following validation, the biomarker is expected to have clinical utility by better stratifying subjects for annual lung cancer screening compared to current demographic criteria alone.

Wieczorek E, Jablonowski Z, Tomasik B, et al.
Different Gene Expression and Activity Pattern of Antioxidant Enzymes in Bladder Cancer.
Anticancer Res. 2017; 37(2):841-848 [PubMed] Related Publications
The aim of this study was to evaluate the possible role in and contribution of antioxidant enzymes to bladder cancer (BC) etiology and recurrence after transurethral resection (TUR). We enrolled 40 patients with BC who underwent TUR and 100 sex- and age-matched healthy controls. The analysis was performed at diagnosis and recurrence, taking into account the time of recurrence. Gene expression of catalase (CAT), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (SOD2) was determined in peripheral blood leukocytes. The activity of glutathione peroxidase 3 (GPX3) was examined in plasma, and GPX1 and copper-zinc containing superoxide dismutase 1 (SOD1) in erythrocytes. SOD2 and GPX1 expression and GPX1 and SOD1 activity were significantly higher in patients at diagnosis of BC in comparison to controls. In patients who had recurrence earlier than 1 year from TUR, CAT and SOD2 expression was lower (at diagnosis p=0.024 and p=0.434, at recurrence p=0.022 and p=0.010), while the GPX1 and GPX3 activity was higher (at diagnosis p=0.242 and p=0.394, at recurrence p=0.019 and p=0.025) compared to patients with recurrence after 1 year from TUR. This study revealed that the gene expression and activity of the antioxidant enzymes are elevated in blood of patients with BC, although a low expression of CAT might contribute to the recurrence of BC, in early prognosis.

Hadami K, Ameziane El Hassani R, Ameur A, et al.
Association between GPX1 Pro189Leu polymorphism and the occurrence of bladder cancer in Morocco.
Cell Mol Biol (Noisy-le-grand). 2016; 62(14):38-43 [PubMed] Related Publications
Worldwide, Bladder cancer is the most frequent male malignancy. It is the third most common male malignancy in Morocco. The risk factors for developing bladder cancer are multiples including dietary conditions, environmental exposure and oxidative stress. GPX1 gene encoding for the human cellular antioxidant enzyme glutathione peroxidase1 is a key factor in the cell detoxification process. GPX1 Pro198Leu polymorphism is associated with a decrease of enzyme activity and may contribute to bladder cancer susceptibility. The present case-control study was planned to assess the presence of GPX1 Pro198Leu polymorphism in Moroccan population to determine whether it is associated with the risk of developing bladder cancer in Moroccan patients. A total of 32 patients with bladder cancer and 40 healthy controls were enrolled. Genotyping of the GPX1 Pro198Leu polymorphism was carried out by PCR amplification and DNA sequencing. Pro198Leu polymorphism was observed in both bladder cancer patients and healthy controls. No significant association between the polymorphism and bladder cancer occurrence was found (Pro/Leu vs. Pro/Pro: p=0.425; Leu vs. Pro: p=0.435). For the analysis of Pro198Leu polymorphism and progression of bladder cancer, no association was observed neither for stages (Pro/Leu vs. Pro/Pro: p=0.500; Leu vs. Pro: p=0.500) nor grades (Pro/Leu vs. Pro/Pro: p=0.415; Leu vs. Pro: p=0.427). Our results clearly showed no significant association between Pro198Leu polymorphism and risk of bladder cancer in our population, suggesting that the effect of this polymorphism on bladder cancer development might be a result of a combination with other genetic alterations and/or non-genetic variables such as diet and lifestyle factors.

Chan JS, Tan MJ, Sng MK, et al.
Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress.
Cell Death Dis. 2017; 8(1):e2562 [PubMed] Free Access to Full Article Related Publications
Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H

Ekoue DN, He C, Diamond AM, Bonini MG
Manganese superoxide dismutase and glutathione peroxidase-1 contribute to the rise and fall of mitochondrial reactive oxygen species which drive oncogenesis.
Biochim Biophys Acta Bioenerg. 2017; 1858(8):628-632 [PubMed] Free Access to Full Article Related Publications
Reactive oxygen species (ROS) largely originating in the mitochondria play essential roles in the metabolic and (epi)genetic reprogramming of cancer cell evolution towards more aggressive phenotypes. Recent studies have indicated that the activity of superoxide dismutase (SOD2) may promote tumor progression by serving as a source of hydrogen peroxide (H

Schlörmann W, Lamberty J, Lorkowski S, et al.
Chemopreventive potential of in vitro fermented nuts in LT97 colon adenoma and primary epithelial colon cells.
Mol Carcinog. 2017; 56(5):1461-1471 [PubMed] Related Publications
Due to their beneficial nutritional profile the consumption of nuts contributes to a healthy diet and might reduce colon cancer risk. To get closer insights into potential mechanisms, the chemopreventive potential of different in vitro fermented nut varieties regarding the modulation of genes involved in detoxification (CAT, SOD2, GSTP1, GPx1) and cell cycle (p21, cyclin D2) as well as proliferation and apoptosis was examined in LT97 colon adenoma and primary epithelial colon cells. Fermentation supernatants (FS) of nuts significantly induced mRNA expression of CAT (up to 4.0-fold), SOD2 (up to 2.5-fold), and GSTP1 (up to 2.3-fold), while GPx1 expression was significantly reduced by all nut FS (0.8 fold on average). Levels of p21 mRNA were significantly enhanced (up to 2.6-fold), whereas all nut FS significantly decreased cyclin D2 expression (0.4-fold on average). In primary epithelial cells, expression of CAT (up to 3.5-fold), GSTP1 (up to 3.0-fold), and GPx1 (up to 3.9-fold) was increased, whereas p21 and cyclin D2 levels were not influenced. Nut FS significantly inhibited growth of LT97 cells and increased levels of early apoptotic cells (8.4% on average) and caspase 3 activity (4.6-fold on average), whereas caspase 3 activity was not modulated in primary colon cells. The differential modulation of genes involved in detoxification and cell cycle together with an inhibition of proliferation and induction of apoptosis in adenoma cells might contribute to chemopreventive effects of nuts regarding colon cancer.

Lan X, Xing J, Gao H, et al.
Decreased Expression of Selenoproteins as a Poor Prognosticator of Gastric Cancer in Humans.
Biol Trace Elem Res. 2017; 178(1):22-28 [PubMed] Related Publications
The aim of the present study was to analyze the selenoprotein expression levels in gastric cancer patients. We enrolled 40 patients (29 males, 11 females) who were recently diagnosed with gastric cancer and 50 healthy people (30 males, 20 females) as controls. The expression of 25 selenoprotein genes (Dio1, Dio2, Dio3, Gpx1, Gpx2, Gpx3, Gpx4, Gpx6, SelH, SelI, SelK, SelM, SelN, SelO, SelP, SelS, SelT, SelV, SelW, SelX, Sel15, Sps2, TR1, TR2, and TR3) in human gastric cancer tissues, para-carcinoma tissues, adjacent normal gastric tissues, erythrocytes, and lymphocytes in the gastric cancer group and healthy control group was analyzed by qRT-PCR. Here, we showed that among the 25 selenoproteins, 13 selenoproteins in erythrocytes (Gpx1, Gpx4, Sel15, TR1, TR2, SelH, SelK, SelM, SelO, SelS, SelV, SelW, and Sps2), 15 selenoproteins in lymphocytes (Gpx1, Gpx4, Sel15, TR1, TR2, SelH, SelK, SelN, SelO, SelS, SelT, SelV, SelX, SelW, and Sps2) and 13 selenoproteins in gastric cancer and para-carcinoma tissues (Dio1, Dio2, Dio3, Gpx1, Gpx4, Sel15, SelH, SelK, SelM, SelS, SelT, SelW, and Sps2) were significantly decreased (P < 0.05) in the gastric cancer group compared to the control group. In summary, the decreasing expression of selenoprotein genes in gastric cancer patients play an important role in the gastric cancer, although further studies are needed to better understand our findings.

Ekoue DN, Zaichick S, Valyi-Nagy K, et al.
Selenium levels in human breast carcinoma tissue are associated with a common polymorphism in the gene for SELENOP (Selenoprotein P).
J Trace Elem Med Biol. 2017; 39:227-233 [PubMed] Related Publications
Selenium supplementation of the diets of rodents has consistently been shown to suppress mammary carcinogenesis and some, albeit not all, human epidemiological studies have indicated an inverse association between selenium and breast cancer risk. In order to better understand the role selenium plays in breast cancer, 30 samples of tumor tissue were obtained from women with breast cancer and analyzed for selenium concentration, the levels of several selenium-containing proteins and the levels of the MnSOD anti-oxidant protein. Polymorphisms within the genes for these same proteins were determined from DNA isolated from the tissue samples. There was a wide range of selenium in these tissues, ranging from 24 to 854ng/gm. The selenium levels in the tissues were correlated to the genotype of the SELENOP selenium carrier protein, but not to other proteins whose levels have been reported to be responsive to selenium availability, including GPX1, SELENOF and SBP1. There was an association between a polymorphism in the gene for MnSOD and the levels of the encoded protein. These studies were the first to examine the relationship between selenium levels, genotypes and protein levels in human tissues. Furthermore, the obtained data provide evidence for the need to obtain data about the effects of selenium in breast cancer by examining samples from that particular tissue type.

Vrzal R, Illes P, Dvorak Z
Transplant drugs affect the expression of phase II and antioxidant enzymes in human carcinoma cells HepG2 but not in primary cultures of human hepatocytes: In vitro comparative study.
Pharmacol Rep. 2016; 68(5):1008-14 [PubMed] Related Publications
BACKGROUND: We carried out a test whether or not transplant drugs such as cyclosporine A, Rapamycin (Sirolimus), Tacrolimus, Everolimus and Mycophenolate mofetil affects the expression of phase II enzymes comprising of UDP-glucuronosyltransferases (UGTs) and glutathione-S-transferases (GSTs), and antioxidant enzymes that consist of glutathione reductase (GSR), glutathione peroxidase 1 (GPX1) and heme-oxygenase 1 (HMOX1).
METHODS: Experiments were performed in primary cultures of human hepatocytes and in human hepatocarcinoma HepG2 cells, the models of metabolically competent and incompetent cells, respectively. We used quantitative real-time PCR.
RESULTS: We found that none of the tested compounds affected the expression of investigated genes in human hepatocytes. On the other hand, Mycophenolate mofetil induced GPX1 mRNA, although it suppressed mRNA level of UGT1A4/1A9/2B7/2B10, GSTA1/O1/T1, GSR and HMOX1 in HepG2 cells.
CONCLUSION: We showed that the tested transplant drugs have no effect on the expression of selected phase II and antioxidant enzymes in human hepatocytes. Nevertheless, the experiments carried out in two common and frequently used in vitro cellular models, we emphasize that finding based solely on carcinoma cells must be taken with caution when transposing to in vivo situations.

Coskun C, Verim A, Farooqi AA, et al.
Are there possible associations between MnSOD and GPx1 gene variants for laryngeal cancer risk or disease progression?
Cell Mol Biol (Noisy-le-grand). 2016; 62(5):25-30 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is a multifaceted and genomically complex disease and cellular and preclinical studies have demystified wide ranging molecular mechanisms which underpin its development and progression and resistance against wide ranging molecular therapeutics. Oxidative stress is a widely studied molecular mechanism and reportedly involved in carcinogenesis. Increasingly it is being realized that accumulation of Reactive Oxygen Species (ROS) activates defensive mechanism to counteract oxidative stress induced damage. Manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx) are important members of defensive machinery. We investigated whether the polymorphisms of MnSOD (Ala-9Val, rs4880) and GPx1 (Pro198Leu, rs1050450) are associated with LSCC and also evaluated possible interactions between these polymorphisms and various lifestyle factors or pathological features of patients. For this purpose, 67 LSCC patients and 73 healty controls were enrolled. Molecular assessment of MnSOD and GPx1 variants were determined with polymerase chain reaction-restriction fragment length polymorphism techniques. We found that the frequency of both heterozygous PL genotype and P allele was considerably higher in patients with advanced tumor stage (T3/T4) than in those with early tumor stage (T1/T2) (OR= 5.106; 95% CI=1.372-19.004; p<0.001, OR=5.787; 95% CI =1.564-21.414; p<0.001 respectively). Although the frequency of ValVal/LL combine genotype was significantly decreased (OR=0.204, 95% CI=0.055-0.760; p=0.021), the frequency of ValAla/PL combine genotypes was higher in patients with stage T3/T4 than in those patients with stage T1/T2 (p=0.027). Consequently, we have concluded that variants of GPx1 and MnSOD should not be considered as a risk factor of LSCC, only may be accepted as a prognostic markers. Use of new technologies such as metabolomics and deep DNA sequencing will prove to be helpful in developing a deeper knowledge related to how cancer cell metabolism adapts and provides a buffer against increased oxidative stress.

Lenormand C, Couteau J, Nouhaud FX, et al.
Predictive Value of NRAMP1 and HGPX1 Gene Polymorphism for Maintenance BCG Response in Non-muscle-invasive Bladder Cancer.
Anticancer Res. 2016; 36(4):1737-43 [PubMed] Related Publications
AIM: To assess the potential predictive value of natural resistance-associated macrophage protein 1 (NRAMP1) and human glutathione peroxidase 1 (hGPX1) polymorphism in non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG) instillation, we conducted an original ancillary multicenter study.
PATIENTS AND METHODS: We evaluated patients included in the multicenter URO-BCG 4 trial, who received three weekly instillations of one-third dose BCG every 6 months (group I) or two weekly instillations every 3 months (group II) for 3 years. For clinical evaluation we also evaluated tumor recurrence and muscle progression. NRAMP1 and hGPX1 polymorphism analyses were performed on blood DNA. NRAMP1 exon 15 and hGPX1 exon 1c were amplified using Type-it Microsatellite PCR Kit® for multiplex polymerase chain reaction.
RESULTS: From June 2004 to April 2010, 146 randomized patients were included in this retrospective study. Blood samples were obtained from 107 patients. With 36 months of follow-up, 13.6% of patients had a tumor recurrence and muscle-invasive progression was observed in 4.3% of patients. Concerning NRAMP1 D543N polymorphism, patients with allele A had no tumor recurrence or muscle-invasive progression. No significant difference was observed in gene polymorphism distribution between groups I and II. Moreover, we did not observe any significant association of gene polymorphisms, tumor recurrence or muscle-invasive progression, event time and disease-free survival.
CONCLUSION: Our results suggest that no significant difference was found for NRAMP1 and hGPX1 gene polymorphisms associated with recurrence time, muscle invasion frequency and disease-free survival, nevertheless, we observed that the NRAMP1 D543N GG genotype group had a shorter time to tumor recurrence.

Sousa VC, Carmo RF, Vasconcelos LR, et al.
Association of Catalase and Glutathione Peroxidase 1 Polymorphisms with Chronic Hepatitis C Outcome.
Ann Hum Genet. 2016; 80(3):145-53 [PubMed] Related Publications
The hepatic damage caused by hepatitis C virus (HCV) infection is associated with the host immune response and viral regulatory factors. Catalase (CAT) and glutathione peroxidase 1 (GPX1) are antioxidant enzymes located in the peroxisomes and mitochondria, respectively, and are responsible for the control of intracellular hydrogen peroxide levels. Polymorphisms in CAT (C-262T) and GPX1 (Pro198Leu) are correlated with serum levels and enzyme activity. This study aimed to investigate the association of genetic polymorphisms of CAT C-262T (rs1001179) and GPX1 Pro198Leu (rs1050450) with different stages of liver fibrosis and development of hepatocellular carcinoma (HCC). This study included 445 patients with chronic hepatitis C, of whom 139 patients had mild fibrosis (F0-F1), 200 had moderate/severe fibrosis (F2-F4), and 106 had HCC. Genotyping of SNPs was performed by real-time PCR using TaqMan probes. The Pro/Pro genotype of GPX1 was significantly associated with fibrosis severity, HCC, Child Pugh score, and BCLC staging. Additionally, patients carrying both CT+TT genotypes in the CAT gene and the Pro/Pro genotype in the GPX1 gene had higher risk for developing moderate/severe fibrosis or HCC (p = 0.009, OR 2.40 and p = 0.002, OR 3.56, respectively). CAT and GPX1 polymorphisms may be implicated in the severity of liver fibrosis and HCC caused by HCV.

Gonçalves AC, Alves R, Baldeiras I, et al.
Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis.
Mol Carcinog. 2017; 56(1):130-148 [PubMed] Related Publications
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) share common features: elevated oxidative stress, DNA repair deficiency, and aberrant DNA methylation. We performed a hospital-based case-control study to evaluate the association in variants of genes involved in oxidative stress, folate metabolism, DNA repair, and DNA methylation with susceptibility and prognosis of these malignancies. To that end, 16 SNPs (one per gene: CAT, CYBA, DNMT1, DNMT3A, DNMT3B, GPX1, KEAP1, MPO, MTRR, NEIL1, NFE2F2, OGG1, SLC19A1, SOD1, SOD2, and XRCC1) were genotyped in 191 patients (101 MDS and 90 AML) and 261 controls. We also measured oxidative stress (reactive oxygen species/total antioxidant status ratio), DNA damage (8-hydroxy-2'-deoxyguanosine), and DNA methylation (5-methylcytosine) in 50 subjects (40 MDS and 10 controls). Results showed that five genes (GPX1, NEIL1, NFE2L2, OGG1, and SOD2) were associated with MDS, two (DNMT3B and SLC19A1) with AML, and two (CYBA and DNMT1) with both diseases. We observed a correlation of CYBA TT, GPX1 TT, and SOD2 CC genotypes with increased oxidative stress levels, as well as NEIL1 TT and OGG1 GG genotypes with higher DNA damage. The 5-methylcytosine levels were negatively associated with DNMT1 CC, DNMT3A CC, and MTRR AA genotypes, and positively with DNMT3B CC genotype. Furthermore, DNMT3A, MTRR, NEIL1, and OGG1 variants modulated AML transformation in MDS patients. Additionally, DNMT3A, OGG1, GPX1, and KEAP1 variants influenced survival of MDS and AML patients. Altogether, data suggest that genetic variability influence predisposition and prognosis of MDS and AML patients, as well AML transformation rate in MDS patients. © 2016 Wiley Periodicals, Inc.

Ko BW, Han J, Heo JY, et al.
Metabolic characterization of imatinib-resistant BCR-ABL T315I chronic myeloid leukemia cells indicates down-regulation of glycolytic pathway and low ROS production.
Leuk Lymphoma. 2016; 57(9):2180-8 [PubMed] Related Publications
Long-term imatinib treatment induces drug-resistant chronic myeloid leukemia (CML) cells harboring T315I gate keeper mutation of breakpoint cluster region (BCR)-ABL oncogenic kinase. However, although cell proliferation is coupled with cellular energy status in CML carcinogenesis, the metabolic characteristics of T315I-mutant CML cells have never been investigated. Here, we analyzed cell proliferation activities and metabolic phenotypes, including cell proliferation, oxygen consumption, lactate production, and redox state in the KBM5 (imatinib-sensitive) and KBM5-T315I (imatinib-resistant) CML cell lines. Interestingly, KBM5-T315I cells showed decreased cell proliferation, lactate production, fatty acid synthesis, ROS production, and down regulation of mRNA expression related to ROS scavengers, such as SOD2, catalase, GCLm, and GPx1. Taken together, our data demonstrate that the lower growth ability of KBM5-T315I CML cells might be related to the decreased expression of glycolysis-related genes and ROS levels, and this will be used to identify therapeutic targets for imatinib resistance in CML.

Bănescu C, Iancu M, Trifa AP, et al.
From Six Gene Polymorphisms of the Antioxidant System, Only GPX Pro198Leu and GSTP1 Ile105Val Modulate the Risk of Acute Myeloid Leukemia.
Oxid Med Cell Longev. 2016; 2016:2536705 [PubMed] Free Access to Full Article Related Publications
Oxidative stress might contribute to the occurrence of cancers, including the hematological ones. Various genetic polymorphisms were shown to increase the quantity of reactive oxygen species, a phenomenon that is able to induce mutations and thus promote cancers. The purpose of the study was to evaluate the association between CAT C262T, GPX1 Pro198Leu, MnSOD Ala16Val, GSTM1, GSTT1, and GSTP1 Ile105Val gene polymorphisms and acute myeloid leukemia risk, in a case-control study comprising 102 patients and 303 controls. No association was observed between AML and variant genotypes of CAT, MnSOD, GSTM1, and GSTT1 polymorphisms. Our data revealed a statistically significant difference regarding the frequencies of GPX1 Pro198Leu and GSTP1 Ile105Val variant genotypes between AML patients and controls (p < 0.001). Our results showed no association in the distribution of any of the CAT C262T, GPX1 Pro198Leu, GSTM1, GSTT1, and GSTP1 polymorphisms regarding age, gender, FAB subtype, cytogenetic risk groups, FLT3 and DNMT3 gene mutations, and overall survival. Our data suggests that the presence of variant allele and genotype of GPX1 Pro198Leu and GSTP1 Ile105Val gene polymorphisms may modulate the risk of developing AML.

Huang Z, Liu Y, Huang Z, et al.
1,25-Dihydroxyvitamin D3 alleviates salivary adenoid cystic carcinoma progression by suppressing GPX1 expression through the NF-κB pathway.
Int J Oncol. 2016; 48(3):1271-9 [PubMed] Related Publications
1,25-Dihydroxyvitamin D3 (1,25D3) is the active form of vitamin D with antineoplastic effects. The glutathione peroxidase-1 (GPX1) gene is associated with tumour progression. The present study aimed to explore the role of GPX1 in 1,25D3-mediated progression of salivary adenoid cystic carcinoma (SACC). Downregulating GPX1 expression inhibited SACC cell proliferation, chemoresistance, motility, and uPA secretion, but promoted apoptosis via the NF-κB pathway. Pre-processing 1,25D3 inhibited expression of NF-κB/GPX1/uPA, which subsequently suppressed cell motility and cisplatin-resistance in ACC-2 cells. In conclusion, 1,25D3 works as a modifier of NF-κB/GPX1/uPA expression, inhibiting cisplatin-resistance and cell invasive ability of SACC cells. The present study comprehensively elucidated the potential mechanism underlying the effects of vitamin D on chemoresistance and invasive potential in SACC.

Zmorzyński S, Świderska-Kołacz G, Koczkodaj D, Filip AA
Significance of Polymorphisms and Expression of Enzyme-Encoding Genes Related to Glutathione in Hematopoietic Cancers and Solid Tumors.
Biomed Res Int. 2015; 2015:853573 [PubMed] Free Access to Full Article Related Publications
Antioxidant compounds such as glutathione and its enzymes have become the focus of attention of medical sciences. Glutathione, a specific tripeptide, is involved in many intercellular processes. The glutathione concentration is determined by the number of GAG repeats in gamma-glutamylcysteine synthetase. GAG polymorphisms are associated with an increased risk of schizophrenia, berylliosis, diabetes, lung cancer, and nasopharyngeal tumors. Cancer cells with high glutathione concentration are resistant to chemotherapy treatment. The oxidized form of glutathione is formed by glutathione peroxidases (GPXs). The changes in activity of GPX1, GPX2, and GPX3 isoforms may be associated with the development of cancers, for example, prostate cancer or even colon cancer. Detoxification of glutathione conjugates is possible due to activity of glutathione S-transferases (GSTs). Polymorphisms in GSTM1, GSTP1, and GSTO1 enzymes increase the risk of developing breast cancer and hepatocellular carcinoma. Gamma-glutamyl transpeptidases (GGTs) are responsible for glutathione degradation. Increased activity of GGT correlates with adverse prognosis in patients with breast cancer. Studies on genes encoding glutathione enzymes are continued in order to determine the correlation between DNA polymorphisms in cancer patients.

Pronina IV, Loginov VI, Burdennyy AM, et al.
Expression and DNA methylation alterations of seven cancer-associated 3p genes and their predicted regulator miRNAs (miR-129-2, miR-9-1) in breast and ovarian cancers.
Gene. 2016; 576(1 Pt 3):483-91 [PubMed] Related Publications
The methylation of promoter CpG islands and interactions between microRNAs (miRNAs) and messenger RNAs (mRNAs) of target genes are considered two crucial epigenetic mechanisms for inducing gene and pathway deregulation in tumors. Here, the expression levels of seven cancer-associated 3p genes (RASSF1(isoform A), RARB(isoform 2), SEMA3B, RHOA, GPX1, NKIRAS1, and CHL1) and their predicted regulator miRNAs (miR-129-2, miR-9-1) were analyzed in breast (BC, 40 samples) and ovarian (OC, 14 samples) cancers using RT-PCR and qPCR. We first revealed a negative correlation between the level of the miR-129-2 precursor and RASSF1(A) and GPX1 mRNA levels in BC (Spearman's correlation coefficient (rs) was − 0.26 in both cases). Similar results were observed for the miR-129-2 precursor and the RASSF1(A), GPX1, RARB(2), and CHL1 genes in OC (rs was in the range − 0.48 to − 0.54). Using methylation-specific PCR, a significant correlation was shown between promoter hypermethylation and the down-regulation of the RASSF1(A), GPX1, RARB(2), SEMA3B, MIR-129-2, and MIR-9-1 genes in BC (rs = 0.41 to 0.75) and of the RASSF1(A) gene in OC (rs = 0.67). We first demonstrated a high hypermethylation frequency of MIR-129-2 and SEMA3B (up to 45 to 48%) in both BC (69 samples) and OC (41 samples). Moreover, we observed a positive correlation between the hypermethylation of MIR-129-2 and the up-regulation of the RASSF1(A) and GPX1 genes in BC (rs = 0.38 and 0.42, respectively). QPCR analysis of the expression of RASSF1(A) and mature miR-129-2 in additional BC sample set (24 samples) revealed a negative correlation between them (rs = − 0.41) that strengthened the results obtained during the analysis of miR-129-2 precursor level. In summary, the obtained data indicate the involvement of methylation in the down-regulation of the studied coding and miRNA genes and suggest the involvement of miR-129-2 in the deregulation of RASSF1(A) via a direct interaction or/and mediators in common pathways (according to KEGG, Gene Ontology (FDR < 0.01), and GeneCards data) in the examined gynecological tumors.

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