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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2354-2363. Prepublished online as a Blood First Edition Paper on October 11, 2005; DOI 10.1182/blood-2005-06-2536. This Article Full Text (PDF) All Versions of this Article: 2005-06-2536v1 107/6/2354    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sors, A. Articles by Michel, L. Search for Related Content PubMed PubMed Citation Articles by Sors, A. Articles by Michel, L. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 27, 2005 Accepted September 25, 2005 Down-regulating Constitutive Activation of the NF-B Canonical Pathway Overcomes the Resistance of Cutaneous T cell Lymphoma to Apoptosis Aurore Sors, Francette Jean-Louis, Claire Pellet, Liliane Laroche, Louis Dubertret, Gilles Courtois, Herve Bachelez, and Laurence Michel* Skin Research Institute and Department of Dermatology 1, INSERM U697. Hopital Saint-Louis, PARIS, France Department of Immuno-Dermatologie, Hopital Avicenne, Bobigny, France * Corresponding author; email: laurence.michel{at}stlouis.inserm.fr. Constitutive activation of the NF-B pathway has been shown to be involved in the resistance of tumor cells to apoptosis in several human malignancies of the hematopoietic lineage. By using EMSA and confocal microscopic analysis, we demonstrate that NF-B is constitutively activated in cutaneous T-cell lymphoma (CTCL) cell lines HuT-78, MyLa and SeAx and in peripheral blood lymphocytes (PBLs) from patients with Sezary syndrome (SS) presenting a high ratio of tumor cells, with evidence of p50 and RelA/p65 in DNA-linked complexes. Transfection of SeAx line with a B/luciferase reporter plasmid showed that translocated NF-B complexes were functional. Selective inhibition of NF-B, by transfecting CTCL cell lines with a super-repressor form of IB, lead to apoptosis. We evidenced down regulation of NF-B activation and induction of CTCL cell apoptosis in the presence of proteasome 26S inhibitors ALLN, MG132 and bortezomib. Bortezomib at nanomolar concentrations inhibited constitutive activation of NF-B and induced apoptosis of CTCL cells, with evidence of an up-regulation of Bax expression. These results demonstrate the key role played by NF-B in the resistance of CTCL to apoptosis and suggest that bortezomib might be useful for the treatment of patients with advanced stages of CTCL refractory to standard antineoplastic chemotherapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Caprini, C. Cristofoletti, D. Arcelli, P. Fadda, M. H. Citterich, F. Sampogna, A. Magrelli, F. Censi, P. Torreri, M. Frontani, et al. Identification of Key Regions and Genes Important in the Pathogenesis of Sezary Syndrome by Combining Genomic and Expression Microarrays Cancer Res., November 1, 2009; 69(21): 8438 - 8446. [Abstract] [Full Text] [PDF] T. Krejsgaard, C. S. Vetter-Kauczok, A. Woetmann, H. Kneitz, K. W. Eriksen, P. Lovato, Q. Zhang, M. A. Wasik, C. Geisler, E. Ralfkiaer, et al. Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma Blood, June 4, 2009; 113(23): 5896 - 5904. [Abstract] [Full Text] [PDF] C.-D. Klemke, D. Brenner, E.-M. Weiss, M. Schmidt, M. Leverkus, K. Gulow, and P. H. Krammer Lack of T-Cell Receptor-Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death Cancer Res., May 15, 2009; 69(10): 4175 - 4183. [Abstract] [Full Text] [PDF] M. K. Kiessling, C. D. Klemke, M. M. Kaminski, I. E. Galani, P. H. Krammer, and K. Gulow Inhibition of Constitutively Activated Nuclear Factor-{kappa}B Induces Reactive Oxygen Species- and Iron-Dependent Cell Death in Cutaneous T-Cell Lymphoma Cancer Res., March 15, 2009; 69(6): 2365 - 2374. [Abstract] [Full Text] [PDF] A. Tun-Kyi, J. -Z. Qin, P. A. Oberholzer, A. A. Navarini, J. C. Hassel, R. Dummer, and U. Dobbeling Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model Ann. Onc., August 1, 2008; 19(8): 1488 - 1494. [Abstract] [Full Text] [PDF] W.-L. Zhao, Y.-Y. Liu, Q.-L. Zhang, L. Wang, C. Leboeuf, Y.-W. Zhang, J. Ma, J.-F. Garcia, Y.-P. Song, J.-M. Li, et al. PRDM1 is involved in chemoresistance of T-cell lymphoma and down-regulated by the proteasome inhibitor Blood, April 1, 2008; 111(7): 3867 - 3871. [Abstract] [Full Text] [PDF] A. Sors, F. Jean-Louis, E. Begue, L. Parmentier, L. Dubertret, M. Dreano, G. Courtois, H. Bachelez, and L. Michel Inhibition of I{kappa}B Kinase Subunit 2 in Cutaneous T-Cell Lymphoma Down-Regulates Nuclear Factor-{kappa}B Constitutive Activation, Induces Cell Death, and Potentiates the Apoptotic Response to Antineoplastic Chemotherapeutic Agents Clin. Cancer Res., February 1, 2008; 14(3): 901 - 911. [Abstract] [Full Text] [PDF] P. L. Zinzani, G. Musuraca, M. Tani, V. Stefoni, E. Marchi, M. Fina, C. Pellegrini, L. Alinari, E. Derenzini, A. de Vivo, et al. Phase II Trial of Proteasome Inhibitor Bortezomib in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma J. Clin. 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