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Blood, 15 January 2007, Vol. 109, No. 2, pp. 720-728. Prepublished online as a Blood First Edition Paper on September 26, 2006; DOI 10.1182/blood-2006-05-024372. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-05-024372v1 109/2/720    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Chatterjee, M. Articles by Bargou, R. C. Search for Related Content PubMed PubMed Citation Articles by Chatterjee, M. Articles by Bargou, R. C. Related Collections Neoplasia Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90 and ß in multiple myeloma cells, which critically contribute to tumor-cell survival Manik Chatterjee1,2,, Sarika Jain1,2, Thorsten Stühmer1, Mindaugas Andrulis3, Ute Ungethüm4, Ralf-Jürgen Kuban4, Heike Lorentz1, Kurt Bommert1, Max Topp1, Doris Krämer1, Hans Konrad Müller-Hermelink3, Hermann Einsele1, Axel Greiner3, and Ralf C. Bargou1 1 Department of Internal Medicine II, Division of Hematology, University Hospital of Würzburg, Germany; 2 Robert Rössle Cancer Clinic at the Max Delbrück Center for Molecular Medicine, Berlin, Germany; 3 Institute of Pathology, University Hospital of Würzburg, Germany; and 4 Laboratory for Functional Genomics, Charité, University Medicine Berlin, Germany The combined blockade of the IL-6R/STAT3 and the MAPK signaling pathways has been shown to inhibit bone marrow microenvironment (BMM)–mediated survival of multiple myeloma (MM) cells. Here, we identify the molecular chaperones heat shock proteins (Hsp) 90 and ß as target genes of both pathways. The siRNA-mediated knockdown of Hsp90 or treatment with the novel Hsp90 inhibitor 17-DMAG attenuated the levels of STAT3 and phospho-ERK and decreased the viability of MM cells. Although knockdown of Hsp90ß—unlike knockdown of Hsp90—was sufficient to induce apoptosis, this effect was strongly increased when both Hsp90s were targeted, indicating a cooperation of both. Given the importance of the BMM for drug resistance and MM-cell survival, apoptosis induced by Hsp90 inhibition was not mitigated in the presence of bone marrow stromal cells, osteoclasts, or endothelial cells. These observations suggest that a positive feedback loop consisting of Hsp90/ß and major signaling pathways supports the survival of MM cells. Finally, in situ overexpression of both Hsp90 proteins was observed in most MMs but not in monoclonal gammopathy of undetermined significance (MGUS) or in normal plasma cells. Our results underpin a role for Hsp90 and ß in MM pathogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Fionda, A. Soriani, G. Malgarini, M. L. Iannitto, A. Santoni, and M. Cippitelli Heat Shock Protein-90 Inhibitors Increase MHC Class I-Related Chain A and B Ligand Expression on Multiple Myeloma Cells and Their Ability to Trigger NK Cell Degranulation J. Immunol., October 1, 2009; 183(7): 4385 - 4394. [Abstract] [Full Text] [PDF] C. Stuehler, S. Mielke, M. Chatterjee, J. Duell, S. Lurati, F. Rueckert, H. Einsele, R. C. Bargou, and M. S. Topp Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease Blood, September 24, 2009; 114(13): 2829 - 2836. [Abstract] [Full Text] [PDF] Y. Hu, K. Kirito, K. Yoshida, T. Mitsumori, K. Nakajima, Y. Nozaki, S. Hamanaka, T. Nagashima, M. Kunitama, K. Sakoe, et al. Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan Mol. Cancer Ther., August 1, 2009; 8(8): 2329 - 2338. [Abstract] [Full Text] [PDF] S. Wang, G. Tricot, L. Shi, W. Xiong, Z. Zeng, H. Xu, M. Zangari, B. Barlogie, J. D. Shaughnessy Jr, and F. Zhan RAR{alpha}2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma Blood, July 16, 2009; 114(3): 600 - 607. [Abstract] [Full Text] [PDF] F. Cervantes-Gomez, R. Nimmanapalli, and V. Gandhi Transcription Inhibition of Heat Shock Proteins: A Strategy for Combination of 17-Allylamino-17-Demethoxygeldanamycin and Actinomycin D Cancer Res., May 1, 2009; 69(9): 3947 - 3954. [Abstract] [Full Text] [PDF] S. Gattenlohner, T. Stuhmer, E. Leich, M. Reinhard, B. Etschmann, H.-U. Volker, A. Rosenwald, E. Serfling, R. C. Bargou, G. Ertl, et al. Specific Detection of CD56 (NCAM) Isoforms for the Identification of Aggressive Malignant Neoplasms with Progressive Development Am. J. Pathol., April 1, 2009; 174(4): 1160 - 1171. [Abstract] [Full Text] [PDF] U. Banerji Heat Shock Protein 90 as a Drug Target: Some Like It Hot Clin. Cancer Res., January 1, 2009; 15(1): 9 - 14. [Abstract] [Full Text] [PDF] M. Chatterjee, C. Rancso, T. Stuhmer, N. Eckstein, M. Andrulis, C. Gerecke, H. Lorentz, H.-D. Royer, and R. C. Bargou The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma Blood, April 1, 2008; 111(7): 3714 - 3722. [Abstract] [Full Text] [PDF] K. Mahtouk, D. Hose, J. De Vos, J. Moreaux, M. Jourdan, J. F. Rossi, T. Reme, H. Goldschmidt, and B. Klein Input of DNA Microarrays to Identify Novel Mechanisms in Multiple Myeloma Biology and Therapeutic Applications Clin. Cancer Res., December 15, 2007; 13(24): 7289 - 7295. [Abstract] [Full Text] [PDF]

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