title: Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma.
abstract: Burkitt lymphoma is a fast-growing tumor derived from germinal center B cells. It is mainly treated with aggressive chemotherapy, therefore novel therapeutic approaches are needed due to treatment toxicity and developing resistance. Disturbance of red-ox homeostasis has recently emerged as an efficient antitumor strategy. Peroxiredoxins (PRDXs) are thioredoxin-family antioxidant enzymes that scavenge cellular peroxides and contribute to red-ox homeostasis. PRDXs are robustly expressed in various malignancies and critically involved in cell proliferation, differentiation and apoptosis. To elucidate potential role of PRDXs in lymphoma, we studied their expression level in B cell-derived primary lymphoma cells as well as in cell lines. We found that PRDX1 and PRDX2 are upregulated in tumor B cells as compared with normal counterparts. Concomitant knockdown of PRDX1 and PRDX2 significantly attenuated the growth rate of lymphoma cells. Furthermore, in human Burkitt lymphoma cell lines, we isolated dimeric 2-cysteine peroxiredoxins as targets for SK053, a novel thiol-specific small-molecule peptidomimetic with antitumor activity. We observed that treatment of lymphoma cells with SK053 triggers formation of covalent PRDX dimers, accumulation of intracellular reactive oxygen species, phosphorylation of ERK1/2 and AKT and leads to cell cycle arrest and apoptosis. Based on site-directed mutagenesis and modeling studies, we propose a mechanism of SK053-mediated PRDX crosslinking, involving double thioalkylation of active site cysteine residues. Altogether, our results suggest that peroxiredoxins are novel therapeutic targets in Burkitt lymphoma and provide the basis for new approaches to the treatment of this disease.
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Trzeciecka
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Klossowski
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Bajor
authors.affiliation: Department of Immunology, 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
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Gaj
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Muchowicz
authors.affiliation: Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Malinowska
authors.affiliation: Bioinformatics Laboratory, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Czerwoniec
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.|Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Barankiewicz
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Antoni
authors.initials: A
authors.lastname: Domagala
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.|Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw, Warsaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Chlebowska
authors.affiliation: Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.|Department of Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Prochorec-Sobieszek
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Winiarska
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Ostaszewski
authors.affiliation: Institute of Physiology and Pathology of Hearing, Warsaw, Poland.
authors.forename: Iwonna
authors.initials: I
authors.lastname: Gwizdalska
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
authors.affiliation: Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw, Warsaw, Poland.|Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Nowis
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Firczuk
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008689:Methacrylates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000072417:Protein Domains; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C570904:2,6-bis-trifluoromethylbenzoic acid 2-(1-(ethoxycarbonylmethylcarbamoyl)-3-methylbutylcarbamoyl)allyl ester; D000970:Antineoplastic Agents; D004151:Dipeptides; D008689:Methacrylates; D017382:Reactive Oxygen Species; C515940:PRDX1 protein, human; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003545:Cysteine
keywords: Burkitt lymphoma; antioxidant enzymes; peroxiredoxin; therapeutic target; thioredoxin