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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2641-2649. Prepublished online as a Blood First Edition Paper on May 24, 2007; DOI 10.1182/blood-2006-11-053728. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-11-053728v1 110/7/2641    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 Davenport, E. L. Articles by Davies, F. E. Search for Related Content PubMed PubMed Citation Articles by Davenport, E. L. Articles by Davies, F. E. Related Collections Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells Emma L. Davenport1, Hannah E. Moore1, Alan S. Dunlop1, Swee Y. Sharp2, Paul Workman2, Gareth J. Morgan1, and Faith E. Davies1 1 Section of Haemato-Oncology, Cancer Research UK, 2 Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, United Kingdom Plasma cells producing high levels of paraprotein are dependent on the unfolded protein response (UPR) and chaperone proteins to ensure correct protein folding and cell survival. We hypothesized that disrupting client–chaperone interactions using heat shock protein 90 (Hsp90) inhibitors would result in an inability to handle immunoglobulin production with the induction of the UPR and myeloma cell death. To study this, myeloma cells were treated with Hsp90 inhibitors as well as known endoplasmic reticulum stress inducers and proteasome inhibitors. Treatment with thapsigargin and tunicamycin led to the activation of all 3 branches of the UPR, with early splicing of XBP1 indicative of IRE1 activation, upregulation of CHOP consistent with ER resident kinase (PERK) activation, and activating transcription factor 6 (ATF6) splicing. 17-AAG and radicicol also induced splicing of XBP1, with the induction of CHOP and activation of ATF6, whereas bortezomib resulted in the induction of CHOP and activation of ATF6 with minimal effects on XBP1. After treatment with all drugs, expression levels of the molecular chaperones BiP and GRP94 were increased. All drugs inhibited proliferation and induced cell death with activation of JNK and caspase cleavage. In conclusion, Hsp90 inhibitors induce myeloma cell death at least in part via endoplasmic reticulum stress and the UPR death pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Belova, D. R. Brickley, B. Ky, S. K. Sharma, and S. D. Conzen Hsp90 Regulates the Phosphorylation and Activity of Serum- and Glucocorticoid-regulated Kinase-1 J. Biol. Chem., July 4, 2008; 283(27): 18821 - 18831. [Abstract] [Full Text] [PDF] M. Kraus, E. Malenke, J. Gogel, H. Muller, T. Ruckrich, H. Overkleeft, H. Ovaa, E. Koscielniak, J. T. Hartmann, and C. Driessen Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis Mol. Cancer Ther., July 1, 2008; 7(7): 1940 - 1948. [Abstract] [Full Text] [PDF] H. Y. Fu, T. Minamino, O. Tsukamoto, T. Sawada, M. Asai, H. Kato, Y. Asano, M. Fujita, S. Takashima, M. Hori, et al. Overexpression of endoplasmic reticulum-resident chaperone attenuates cardiomyocyte death induced by proteasome inhibition Cardiovasc Res, June 9, 2008; (2008) cvn128v2. [Abstract] [Full Text] [PDF]

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