Side-by-side comparison of recombinant human glutathione peroxidases identifies overlapping substrate specificities for soluble hydroperoxides

Schwarz, Maria; Löser, Alina; Cheng, Qing; Wichmann-Costaganna, Mareike; Schädel, Patrick; Werz, Oliver; Arnér, Elias S.J.; Kipp, Anna P.

doi:10.1016/j.redox.2022.102593

Cited by 21 publications

(24 citation statements)

References 55 publications

(77 reference statements)

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“…We first set out to characterize inhibition of GPX4 by FINs in comparison to the inhibition of GPX1, reasoning that GPX4 inhibitors may also target other GPX isoenzymes. Using recombinant selenoproteins [ 2 , [26] , [27] , [28] ] and a selection of prior art ferroptosis inducing inhibitors [ 3 ] we were initially surprised to find that neither RSL3, ML162, nor ML210 inhibited either GPX isoenzyme ( Fig. 1 A, top panels).…”

Section: Resultsmentioning

confidence: 99%

“…1 A, lower panels). The recombinant selenoproteins used here have high similarity with their native counterparts in terms of structure, enzymatic activity, and substrate specificity, with the main difference being that, mostly due to Gln or Lys suppression, the recombinant proteins have a lower Sec contents [ 2 , 26 ]. However, as only the Sec containing proteins have enzymatic activity these recombinantly produced variants can facilitate the identification of their inhibitors, as was done here.…”

Section: Resultsmentioning

confidence: 99%

“…Glutathione peroxidase 4 (GPX4) is a selenoprotein using glutathione (GSH) and a highly reactive catalytic selenocysteine (Sec) residue to efficiently reduce lipid hydroperoxides, being a substrate specificity that distinguishes it from other GPX isoenzymes [ 1 , 2 ]. Originally named Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPX) because of this eponymous activity, GPX4 has emerged as a key suppressor of the iron-dependent lipid peroxide-triggered mode of cell death named ferroptosis [ 1 , [3] , [4] , [5] , [6] , [7] ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1

Cheff¹,

Huang²,

Scholzen³

et al. 2023

Redox Biology

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1

Cheff¹,

Huang²,

Scholzen³

et al. 2023

Redox Biology

Self Cite

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“…Glutathione peroxidases (GPXs) are selenium-containing enzymes crucial in the defense of oxidative stress by reducing peroxides with the oxidization of glutathione (GSH) to glutathione disul de (GSSG) [18,19]. There are eight GPX family members who have distinct cellular locations and substrate speci cities, contributing to various physiological functions beyond their antioxidant roles [20].…”

Section: Introductionmentioning

confidence: 99%

NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma

Jin,

Lou,

et al. 2024

Preprint

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Background: The activation of nuclear factor erythroid 2–related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. Methods: We systematically investigated the role of NRF2 in HNSCC, ultimately selecting GPX2, which exhibited a marked downregulation, for a detailed mechanistic analysis. Firstly, we knocked out NRF2 by CRISPR-Cas9, and subsequently confirmed by RT-qPCR and Western Blot. The role of NRF2was evaluated through various assays, including cell growth assays, colony formation assays, 3D cultures, cell migration and invasion assessments, ROS detection, and xenograft tumor models. Furthermore, we performed RNA sequencing on NRF2-KO cells compared to NRF2-WT cells identified GPX2 as a downstream target of NRF2. This finding led us to examine the role of GPX2 in the maintenance of cancer stem cells (CSCs). Notably, CSC analysis indicated the involvement of the NOTCH signaling pathway in HNSCC progression, and the critical role of NOTCH3 was confirmed using the serious experimental approaches mentioned earlier. Results: We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining CSCs by up-regulating NOTCH3, a key driver of cancer progression. Conclusions: NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.

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“…It consists of four identical subunits with a molecular weight of 22–23 kDa. There are approximately 208 amino acids in each monomer [ 9 ]. Being a selenoprotein, the selenium within the Gpx-1 protein is formed by the addition of the 21st amino acid, selenocysteine, into the nascent polypeptide chain during the translation process at the UGA stop codon [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Expression of Glutathione Peroxidase 1 (Gpx-1) as an Independent Prognostic Factor in Colon Adenocarcinoma Patients

et al. 2023

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Several studies revealed that expression levels of glutathione peroxidase 1 (Gpx-1) can be associated with cancer development, mainly through its role in hydroperoxide scavenging by regulating intracellular reactive oxygen species (ROS) levels. Therefore, our aim was to investigate the expression of Gpx-1 protein in a population of Polish patients with colon adenocarcinoma in the absence of any therapy prior to radical surgery. The study was carried out using colon tissue from patients with adenocarcinoma of the colon confirmed by histopathological examination. Gpx-1 antibody was used to determine the immunohistochemical expression of Gpx-1. The Chi2 test or Chi2Yatesa test were used to analyse the associations between the immunohistochemical expression of Gpx-1 and clinical parameters. The relationship between Gpx-1 expression, and 5-year patient survival was examined using Kaplan–Meier analysis and the log-rank test. Intracellular localisation of Gpx-1 was detected by the use of transmission electron microscopy (TEM). Western blot analysis was used for the evaluation of Gpx-1 protein expression levels in cancer cell lines in vitro. Immunohistochemical study revealed that the high expression of Gpx-1 was associated with the tumour’s histological grade, proliferating cell nuclear antigen (PCNA) immunohistochemical expression, depth of invasion, and angioinvasion (all p < 0.001) (4). The high immunohistochemical expression of Gpx-1 is correlated with poor prognosis of colon adenocarcinoma patients.

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Side-by-side comparison of recombinant human glutathione peroxidases identifies overlapping substrate specificities for soluble hydroperoxides

Cited by 21 publications

References 55 publications

The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1

The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1

NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma

Immunohistochemical Expression of Glutathione Peroxidase 1 (Gpx-1) as an Independent Prognostic Factor in Colon Adenocarcinoma Patients

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