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Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma

Trzeciecka, Anna and Klossowski, Szymon and Bajor, Małgorzata and Zagozdzon, Radoslaw and Gaj, Pawel and Muchowicz, Angelika and Malinowska, Agata and Czerwoniec, Anna and Barankiewicz, Joanna and Domagala, Antoni and Chlebowska, Justyna and Prochorec-Sobieszek, Monika and Winiarska, Magdalena and Ostaszewski, Ryszard and Gwizdalska, Iwonna and Golab, Jakub and Nowis, Dominika and Firczuk, Małgorzata (2016) Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma. Oncotarget, 7 (2). pp. 1717-1731. ISSN 1949-2553


Official URL: http://doi.org/10.18632/oncotarget.6435


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.

Item Type:Article
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ID Code:1416
Deposited By: Agata Malinowska
Deposited On:09 Nov 2017 09:46
Last Modified:31 Dec 2018 09:41

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