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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3255-3262. Prepublished online as a Blood First Edition Paper on December 21, 2004; DOI 10.1182/blood-2004-10-3984. This Article Full Text (PDF) All Versions of this Article: 2004-10-3984v1 105/8/3255    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 Nencioni, A. Articles by Ballestrero, A. Search for Related Content PubMed PubMed Citation Articles by Nencioni, A. Articles by Ballestrero, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 15, 2004 Accepted December 10, 2004 Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis Alessio Nencioni*, Fei Hua, Christopher P Dillon, Rayka Yokoo, Christoph Scheiermann, Eleonora Barbieri, Ilaria Rocco, Anna Garuti, Sebastian Wesselborg, Claus Belka, Peter Brossart, Franco Patrone, and Alberto Ballestrero Department of Biology, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Internal Medicine, University of Genova, Genova, Italy Department of Biology, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Internal Medicine, University of Genova, Genova, Italy Department of Internal Medicine I, University of Tubingen, Tubingen, Germany Department of Radiation Oncology, University of Tubingen, Tubingen, Germany Department of Hematology, Oncology and Immunology, University of Tubingen, Tubingen, Germany * Corresponding author; email: A.Nencioni{at}gmx.net. Proteasome inhibitors exhibit antitumor activity against malignancies of different histology. Yet, the mechanisms underlying this effect are poorly understood. Recent evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, possibly reducing their cytotoxicity. These include the Bcl-2 family member Mcl-1, whose downregulation has been proposed to initiate apoptosis in response to genotoxic stimuli. In this study, we found that proteasome inhibitors release cyotochrome c and SMAC/Diablo and trigger the subsequent apoptotic cascade in spite of concomitant Mcl-1 increase. However, our data indicate that subtraction of Mcl-1 during apoptosis, while not required for early release of proapoptotic factors, is probably relevant in speeding up cell demise, since RNA interference-mediated Mcl-1 silencing is lethal in lymphoma cells. Consistent with this, the cytotoxic effects of proteasome inhibitors are enhanced when Mcl-1 increase is impeded. Thus, this study identifies Mcl-1 accumulation as an unwanted molecular consequence of exposure to proteasome inhibitors, which slows down their proapoptotic effects. Pharmacological or genetic approaches targeting Mcl-1, including therapeutic RNAi, may increase the effectiveness of these compounds. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mcl-1 reduction: releasing a death brake? Thomas J. Sayers Blood 2005 105: 3005. [Full Text] [PDF] This article has been cited by other articles: F. T. Awan, N. E. Kay, M. E. Davis, W. Wu, S. M. Geyer, N. Leung, D. F. Jelinek, R. C. Tschumper, C. R. Secreto, T. S. Lin, et al. Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab Blood, January 15, 2009; 113(3): 535 - 537. [Abstract] [Full Text] [PDF] A. Shanker, A. D. Brooks, C. A. Tristan, J. W. Wine, P. J. Elliott, H. Yagita, K. Takeda, M. J. Smyth, W. J. Murphy, and T. J. Sayers Treating Metastatic Solid Tumors With Bortezomib and a Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor Agonist Antibody J Natl Cancer Inst, May 7, 2008; 100(9): 649 - 662. [Abstract] [Full Text] [PDF] Y. Dai, S. Chen, L. B. Kramer, V. L. Funk, P. Dent, and S. Grant Interactions between Bortezomib and Romidepsin and Belinostat in Chronic Lymphocytic Leukemia Cells Clin. Cancer Res., January 15, 2008; 14(2): 549 - 558. [Abstract] [Full Text] [PDF] N. Chetoui, K. Sylla, J.-V. Gagnon-Houde, C. Alcaide-Loridan, D. Charron, R. Al-Daccak, and F. Aoudjit Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis Mol. Cancer Res., January 1, 2008; 6(1): 42 - 52. [Abstract] [Full Text] [PDF] P. M. Voorhees, Q. Chen, D. J. Kuhn, G. W. Small, S. A. Hunsucker, J. S. Strader, R. E. Corringham, M. H. Zaki, J. A. Nemeth, and R. Z. Orlowski Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma Clin. Cancer Res., November 1, 2007; 13(21): 6469 - 6478. [Abstract] [Full Text] [PDF] P. Gomez-Bougie, S. Wuilleme-Toumi, E. Menoret, V. Trichet, N. Robillard, M. Philippe, R. Bataille, and M. Amiot Noxa Up-regulation and Mcl-1 Cleavage Are Associated to Apoptosis Induction by Bortezomib in Multiple Myeloma Cancer Res., June 1, 2007; 67(11): 5418 - 5424. [Abstract] [Full Text] [PDF] P. Perez-Galan, G. Roue, N. Villamor, E. Campo, and D. Colomer The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak Blood, May 15, 2007; 109(10): 4441 - 4449. [Abstract] [Full Text] [PDF] S.-R. A. Hussain, C. M. Cheney, A. J. Johnson, T. S. Lin, M. R. Grever, M. A. Caligiuri, D. M. Lucas, and J. C. Byrd Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity Clin. Cancer Res., April 1, 2007; 13(7): 2144 - 2150. [Abstract] [Full Text] [PDF] W.-X. Ding, H.-M. Ni, X. Chen, J. Yu, L. Zhang, and X.-M. Yin A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells Mol. Cancer Ther., March 1, 2007; 6(3): 1062 - 1069. [Abstract] [Full Text] [PDF] N. Gao, L. Kramer, M. Rahmani, P. Dent, and S. Grant The Three-Substituted Indolinone Cyclin-Dependent Kinase 2 Inhibitor 3-[1-(3H-Imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) Kills Human Leukemia Cells via Down-Regulation of Mcl-1 through a Transcriptional Mechanism Mol. Pharmacol., August 1, 2006; 70(2): 645 - 655. [Abstract] [Full Text] [PDF] E. S. Henson, X. Hu, and S. B. Gibson Herceptin Sensitizes ErbB2-Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression Clin. Cancer Res., February 1, 2006; 12(3): 845 - 853. [Abstract] [Full Text] [PDF] P. Perez-Galan, G. Roue, N. Villamor, E. Montserrat, E. Campo, and D. Colomer The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status Blood, January 1, 2006; 107(1): 257 - 264. [Abstract] [Full Text] [PDF] A. L. McCormick, C. D. Meiering, G. B. Smith, and E. S. Mocarski Mitochondrial Cell Death Suppressors Carried by Human and Murine Cytomegalovirus Confer Resistance to Proteasome Inhibitor-Induced Apoptosis J. Virol., October 1, 2005; 79(19): 12205 - 12217. [Abstract] [Full Text] [PDF] A. Nencioni, L. Wille, G. Dal Bello, D. Boy, G. Cirmena, S. Wesselborg, C. Belka, P. Brossart, F. Patrone, and A. Ballestrero Cooperative Cytotoxicity of Proteasome Inhibitors and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Chemoresistant Bcl-2-Overexpressing Cells Clin. Cancer Res., June 1, 2005; 11(11): 4259 - 4265. [Abstract] [Full Text] [PDF]

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