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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 25, 2006 Accepted August 23, 2006 STAT3 and MAPK signaling maintains overexpression of the heat shock proteins 90 and in multiple myeloma cells, which critically contribute to tumor cell survival Manik Chatterjee*, Sarika Jain, Thorsten Stuhmer, Mindaugas Andrulis, Ute Ungethum, Ralf-Jurgen Kuban, Heike Lorentz, Kurt Bommert, Max Topp, Doris Kramer, Hans Konrad Muller-Hermelink, Hermann Einsele, Axel Greiner, and Ralf C Bargou Division of Hematology, University Hospital of Wurzburg, Wurzburg, Germany Institute of Pathology, University Hospital of Wurzburg, Wurzburg, Germany Laboratory for Functional Genomics, Charite, University Medicine, Berlin, Germany * Corresponding author; email: chatterjee_m{at}medizin.uni-wuerzburg.de. 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 protein (Hsp) 90 and as target genes of both pathways. 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 Hsp90 -- 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/ and major signaling pathways supports the survival of MM cells. Finally, in situ overexpression of both Hsp90 proteins was observed in the majority of MM, but not in MGUS or in normal plasma cells. Our results underpin a role for Hsp90 and 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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