title: Adenanthin, a new inhibitor of thiol-dependent antioxidant enzymes, impairs the effector functions of human natural killer cells.
abstract: Natural killer (NK) cells are considered critical components of the innate and adaptive immune responses. Deficiencies in NK cell activity are common, such as those that occur in cancer patients, and they can be responsible for dysfunctional immune surveillance. Persistent oxidative stress is intrinsic to many malignant tumours, and numerous studies have focused on the effects of reactive oxygen species on the anti-tumour activity of NK cells. Indeed, investigations in animal models have suggested that one of the most important thiol-dependent antioxidant enzymes, peroxiredoxin 1 (PRDX1), is essential for NK cell function. In this work, our analysis of the transcriptomic expression pattern of antioxidant enzymes in human NK cells has identified PRDX1 as the most prominently induced transcript out of the 18 transcripts evaluated in activated NK cells. The change in PRDX1 expression was followed by increased expression of two other enzymes from the PRDX-related antioxidant chain: thioredoxin and thioredoxin reductase. To study the role of thiol-dependent antioxidants in more detail, we applied a novel compound, adenanthin, to induce an abrupt dysfunction of the PRDX-related antioxidant chain in NK cells. In human primary NK cells, we observed profound alterations in spontaneous and antibody-dependent NK cell cytotoxicity against cancer cells, impaired degranulation, and a decreased expression of activation markers under these conditions. Collectively, our study pinpoints the unique role for the antioxidant activity of the PRDX-related enzymatic chain in human NK cell functions. Further understanding this phenomenon will prospectively lead to fine-tuning of the novel NK-targeted therapeutic approaches to human disease.
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Siernicka
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Winiarska
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Bajor
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Firczuk
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Muchowicz
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Bobrowicz
authors.affiliation: IBiSA Cancer Immunomonitoring Platform, Institut Paoli Calmettes, Inserm, U1068, CRCM, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Fauriat
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
authors.affiliation: IBiSA Cancer Immunomonitoring Platform, Institut Paoli Calmettes, Inserm, U1068, CRCM, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille Université, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.affiliation: Department of Immunology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.|Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Zagozdzon
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D000975:Antioxidants; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D018384:Oxidative Stress / Q000187:drug effects; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000096:biosynthesis; D013879:Thioredoxins / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D045786:Diterpenes, Kaurane; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; C491203:TXN protein, human; C000600164:adenanthin; D013879:Thioredoxins; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D005978:Glutathione
keywords: degranulation; natural killer cells; oxidative stress; peroxiredoxin; tumour surveillance