Abstract:
: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) 90alpha and beta 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 Hsp90beta-unlike knockdown of Hsp90alpha-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 Hsp90alpha/beta 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 Hsp90alpha and beta in MM pathogenesis.
journal_name
Bloodjournal_title
Bloodauthors
Chatterjee M,Jain S,Stühmer T,Andrulis M,Ungethüm U,Kuban RJ,Lorentz H,Bommert K,Topp M,Krämer D,Müller-Hermelink HK,Einsele H,Greiner A,Bargou RCdoi
10.1182/blood-2006-05-024372subject
Has Abstractpub_date
2007-01-15 00:00:00pages
720-8issue
2eissn
0006-4971issn
1528-0020pii
blood-2006-05-024372journal_volume
109pub_type
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