HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roué, G. Articles by Colomer, D. Search for Related Content PubMed PubMed Citation Articles by Roué, G. Articles by Colomer, D.

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.

This article has been cited by other articles:

				A. Lundqvist, H. Yokoyama, A. Smith, M. Berg, and R. Childs Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells Blood, June 11, 2009; 113(24): 6120 - 6127. [Abstract] [Full Text] [PDF]

				M. Lopez-Guerra, G. Roue, P. Perez-Galan, R. Alonso, N. Villamor, E. Montserrat, E. Campo, and D. Colomer p65 Activity and ZAP-70 Status Predict the Sensitivity of Chronic Lymphocytic Leukemia Cells to the Selective I{kappa}B Kinase Inhibitor BMS-345541 Clin. Cancer Res., April 15, 2009; 15(8): 2767 - 2776. [Abstract] [Full Text] [PDF]

				H. Tanaka, Y. Hoshikawa, T. Oh-hara, S. Koike, M. Naito, T. Noda, H. Arai, T. Tsuruo, and N. Fujita PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-{kappa}B Activation Mol. Cancer Res., April 1, 2009; 7(4): 557 - 569. [Abstract] [Full Text] [PDF]

				G. Roue, M. Lopez-Guerra, P. Milpied, P. Perez-Galan, N. Villamor, E. Montserrat, E. Campo, and D. Colomer Bendamustine Is Effective in p53-Deficient B-Cell Neoplasms and Requires Oxidative Stress and Caspase-Independent Signaling Clin. Cancer Res., November 1, 2008; 14(21): 6907 - 6915. [Abstract] [Full Text] [PDF]

				M. Romagnoli, G. Desplanques, S. Maiga, S. Legouill, M. Dreano, R. Bataille, and S. Barille-Nion Canonical Nuclear Factor {kappa}B Pathway Inhibition Blocks Myeloma Cell Growth and Induces Apoptosis in Strong Synergy with TRAIL Clin. Cancer Res., October 15, 2007; 13(20): 6010 - 6018. [Abstract] [Full Text] [PDF]