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Selective Inhibition of IB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level¹

Hematopathology Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

In an attempt to circumvent the intrinsic resistance of mantle cell lymphoma (MCL) cells to apoptosis, we have analyzed their sensitivity to the extrinsic apoptotic signal triggered by TRAIL. We show here that TRAIL can trigger apoptosis in a majority of MCL cell lines and primary cultures, irrespective of receptor levels, Bcl-2 family members, or caspase regulator expression. MCL sensitivity to TRAIL was closely linked to the activity of the NF-B p50 factor and to the consequent expression of cellular FLIP (c-FLIP), which accumulated into the TRAIL-dependent complex in resistant cells. c-FLIP transient knockdown overcame MCL resistance to TRAIL, while NF-B inhibitors differentially modulated TRAIL cytotoxicity. Indeed, bortezomib increased TRAIL cytotoxic effects in sensitive cells, but led to the intracellular accumulation of c-FLIP, impeding full synergistic interaction. In contrast, the IB kinase inhibitor BMS-345541 led to decreased c-FLIP expression and allowed all MCL samples to undergo TRAIL-mediated apoptosis. These results present the combination of TRAIL stimulation and IB kinase inhibition as a new approach to MCL therapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was financially supported by Fondo de Investigaciones Sanitarias FIS03/0398 (to D.C.), the Lymphoma Research Foundation, European Commission Contracts SLMM-CT-2004-503351, Redes temáticas de Centros: Genómica del cancer (03/10) and Red Estudio de neoplasias linfoides (03/179), Instituto de Salud Carlos III. G.R. and P.P.-G. hold postdoctoral contracts from the c-RED program (Generalitat de Catalunya) and from the Juan de la Cierva program (Ministerio de Educación y Ciencia), respectively. M.L.-G. is the recipient of a predoctoral fellowship from Generalitat de Catalunya.

² Address correspondence and reprint requests to Dr. Dolors Colomer, Hematopathology Unit, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. E-mail address: dcolomer{at}clinic.ub.es

³ Abbreviations used in this paper: MCL, mantle cell lymphoma; DR, death receptor; DISC, death-inducing signaling complex; FADD, Fas-associated death domain; DcR, decoy inhibitory receptor; c-FLIP, cellular FLIP; c-FLIP_S, c-FLIP short form; c-FLIP_L, c-FLIP long form; IKK, IB kinase; IAP, inhibitor of apoptosis protein; XIAP, X-chromosome linked IAP; siRNA, small-interfering RNA.

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