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Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis
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SYSNO ASEP 0398210 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis Author(s) Molinsky, J. (CZ)
Klánová, M. (CZ)
Koc, Michal (UMG-J)
Beranová, Lenka (UMG-J)
Anděra, Ladislav (UMG-J) RID
Ludvíková, Z. (CZ)
Bohmova, M. (CZ)
Gasova, Z. (CZ)
Strnad, Miroslav (UEB-Q) RID, ORCID
Ivánek, R. (CZ)
Trněný, M. (CZ)
Nečas, E. (CZ)
Živný, J. (CZ)
Klener, P. (CZ)Source Title Leukemia & Lymphoma - ISSN 1042-8194
Roč. 54, č. 2 (2013), s. 372-380Number of pages 9 s. Language eng - English Country GB - United Kingdom Keywords roscovitine ; TRAIL ; synergism ; apoptosis ; leukemia ; lymphoma Subject RIV EB - Genetics ; Molecular Biology R&D Projects NS10287 GA MZd - Ministry of Health (MZ) Institutional support UMG-J - RVO:68378050 CEZ AV0Z50380511 - UEB-Q (2005-2011) UT WOS 000313285400027 DOI 10.3109/10428194.2012.710331 Annotation Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2014
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