Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis

0398210 - ÚMG 2014 RIV GB eng J - Journal Article
Molinsky, J. - Klánová, M. - Koc, Michal - Beranová, Lenka - Anděra, Ladislav - Ludvíková, Z. - Bohmova, M. - Gasova, Z. - Strnad, Miroslav - Ivánek, R. - Trněný, M. - Nečas, E. - Živný, J. - Klener, P.
Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
Leukemia & Lymphoma. Roč. 54, č. 2 (2013), s. 372-380. ISSN 1042-8194. E-ISSN 1029-2403
R&D Projects: GA MZd NS10287
Institutional research plan: CEZ:AV0Z50380511
Institutional support: RVO:68378050
Keywords : roscovitine * TRAIL * synergism * apoptosis * leukemia * lymphoma
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 2.605, year: 2013

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.
Permanent Link: http://hdl.handle.net/11104/0228407