|
|
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.
Previous Article | Next Article 
Submitted November 3, 2006
Accepted May 10, 2007
Heat shock protein inhibition is associated with activation of the unfolded protein response (UPR) pathway in myeloma plasma cells
Emma L Davenport, Hannah E Moore, Alan S Dunlop, Swee Y Sharp, Paul Workman, Gareth J Morgan, and Faith E Davies*
Section of Haemato-Oncology, Institute of Cancer Research, Sutton, United Kingdom
Cancer Research UK, Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, United Kingdom
* Corresponding author; email: faith.davies{at}icr.ac.uk.
Plasma cells producing high levels of paraprotein are dependent upon the unfolded protein response (UPR) and chaperone proteins to ensure correct protein folding and cell survival. We hypothesised that disrupting client-chaperone interactions using Hsp90 inhibitors would result in an inability to handle immunoglobulin production with the induction of the UPR and myeloma cell death. In order to study this myeloma cells were treated with Hsp90 inhibitors as well as known ER stress inducers and proteasome inhibitors. Treatment with thapsigargin (TG) and tunicamycin (TM) led to the activation of all three branches of the UPR with early splicing of XBP1 indicative of IRE1 activation, upregulation of CHOP consistent with PERK activation and 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. Following 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 ER 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:

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
S. Saito, A. Furuno, J. Sakurai, A. Sakamoto, H.-R. Park, K. Shin-ya, T. Tsuruo, and A. Tomida
Chemical Genomics Identifies the Unfolded Protein Response as a Target for Selective Cancer Cell Killing during Glucose Deprivation
Cancer Res.,
May 15, 2009;
69(10):
4225 - 4234.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. E. Moore, E. L. Davenport, E. M. Smith, S. Muralikrishnan, A. S. Dunlop, B. A. Walker, D. Krige, A. H. Drummond, L. Hooftman, G. J. Morgan, et al.
Aminopeptidase inhibition as a targeted treatment strategy in myeloma
Mol. Cancer Ther.,
April 1, 2009;
8(4):
762 - 770.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. Bianchi, L. Oliva, P. Cascio, N. Pengo, F. Fontana, F. Cerruti, A. Orsi, E. Pasqualetto, A. Mezghrani, V. Calbi, et al.
The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition
Blood,
March 26, 2009;
113(13):
3040 - 3049.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. M. Schewe and J. A. Aguirre-Ghiso
Inhibition of eIF2{alpha} Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy
Cancer Res.,
February 15, 2009;
69(4):
1545 - 1552.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. S. Raab, I. Breitkreutz, G. Tonon, J. Zhang, P. J. Hayden, T. Nguyen, J. H. Fruehauf, B. K. Lin, D. Chauhan, T. Hideshima, et al.
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling
Blood,
February 12, 2009;
113(7):
1513 - 1521.
[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]
|
 |
|

|
 |

|
 |
 
N. Zaarur, A. B. Meriin, V. L. Gabai, and M. Y. Sherman
Triggering Aggresome Formation: DISSECTING AGGRESOME-TARGETING AND AGGREGATION SIGNALS IN SYNPHILIN 1
J. Biol. Chem.,
October 10, 2008;
283(41):
27575 - 27584.
[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,
September 1, 2008;
79(4):
600 - 610.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. Rao, W. Fiskus, Y. Yang, P. Lee, R. Joshi, P. Fernandez, A. Mandawat, P. Atadja, J. E. Bradner, and K. Bhalla
HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells
Blood,
September 1, 2008;
112(5):
1886 - 1893.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|
|
|