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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.
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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.
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