Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma
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Anna Trzeciecka1, Szymon Klossowski2, Malgorzata Bajor1, Radoslaw Zagozdzon1,3, Pawel Gaj1, Angelika Muchowicz1, Agata Malinowska4, Anna Czerwoniec5, Joanna Barankiewicz1,6, Antoni Domagala1, Justyna Chlebowska1,7, Monika Prochorec-Sobieszek8,9, Magdalena Winiarska1, Ryszard Ostaszewski2, Iwonna Gwizdalska10, Jakub Golab1, Dominika Nowis7,11, Malgorzata Firczuk1
1Department of Immunology, Medical University of Warsaw, Warsaw, Poland
2Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland
3Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
4Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
5Bioinformatics Laboratory, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, Poland
6Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland
7Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw, Warsaw, Poland
8Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
9Department of Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
10Institute of Physiology and Pathology of Hearing, Warsaw, Poland
11Genomic Medicine, Medical University of Warsaw, Warsaw, Poland
Malgorzata Firczuk, e-mail: firstname.lastname@example.org
Keywords: antioxidant enzymes, peroxiredoxin, therapeutic target, Burkitt lymphoma, thioredoxin
Received: May 05, 2015 Accepted: November 16, 2015 Published: November 30, 2015
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.
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