Oncotarget

Research Papers:

Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma

Anna Trzeciecka, Szymon Klossowski, Malgorzata Bajor, Radoslaw Zagozdzon, Pawel Gaj, Angelika Muchowicz, Agata Malinowska, Anna Czerwoniec, Joanna Barankiewicz, Antoni Domagala, Justyna Chlebowska, Monika Prochorec-Sobieszek, Magdalena Winiarska, Ryszard Ostaszewski, Iwonna Gwizdalska, Jakub Golab, Dominika Nowis and Malgorzata Firczuk _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:1717-1731. https://doi.org/10.18632/oncotarget.6435

Metrics: PDF 1238 views  |   HTML 1403 views  |   ?  


Abstract

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

Correspondence to:

Malgorzata Firczuk, e-mail: mfirczuk@wum.edu.pl

Keywords: antioxidant enzymes, peroxiredoxin, therapeutic target, Burkitt lymphoma, thioredoxin

Received: May 05, 2015     Accepted: November 16, 2015     Published: November 30, 2015

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 6435