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STAT3 and MAPK signaling maintains overexpression of the heat shock proteins 90a and b in multiple myeloma cells, which critically contribute to tumor cell survival

Item Type:Article
Title:STAT3 and MAPK signaling maintains overexpression of the heat shock proteins 90a and b in multiple myeloma cells, which critically contribute to tumor cell survival
Creators Name:Chatterjee, M. and Jain, S. and Stuehmer, T. and Andrulis, M. and Ungethuem, U. and Kuban, R.J. and Lorentz, H. and Bommert, K. and Topp, M. and Kramer, D. and Mueller-Hermelink, H. K. and Einsele, H. and Greiner, A. and Bargou, R.C.
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 protein (Hsp) 90alpha and beta 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 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 the majority of MM, but not in MGUS or in normal plasma cells. Our results underpin a role for Hsp90alpha and beta in MM pathogenesis.
Keywords:Apoptosis, Benzoquinones, Cell Line, Cell Survival, Coculture Techniques, Down-Regulation, HSP90 Heat-Shock Proteins, Macrocyclic Lactams, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Multiple Myeloma, Phosphorylation, RNA Interference, Small Interfering RNA, STAT3 Transcription Factor, Signal Transduction, Structure-Activity Relationship
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Volume:109
Number:2
Page Range:720-728
Date:15 January 2007
Official Publication:https://doi.org/10.1182/blood-2006-05-024372
PubMed:View item in PubMed

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