title: STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90alpha and beta in multiple myeloma cells, which critically contribute to tumor-cell survival.
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.
authors.affiliation: Division of Hematology, University Hospital of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. chatterjee_m@medizin.uni-wuerzburg.de
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Sarika
authors.initials: S
authors.lastname: Jain
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stühmer
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.forename: Ute
authors.initials: U
authors.lastname: Ungethüm
authors.forename: Ralf-Jürgen
authors.initials: RJ
authors.lastname: Kuban
authors.forename: Heike
authors.initials: H
authors.lastname: Lorentz
authors.forename: Kurt
authors.initials: K
authors.lastname: Bommert
authors.forename: Max
authors.initials: M
authors.lastname: Topp
authors.forename: Doris
authors.initials: D
authors.lastname: Krämer
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Axel
authors.initials: A
authors.lastname: Greiner
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D020928:Mitogen-Activated Protein Kinases