STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90alpha and beta in multiple myeloma cells, which critically contribute to tumor-cell survival.
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.
Chatterjee
Manik
M
Division of Hematology, University Hospital of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. chatterjee_m@medizin.uni-wuerzburg.de
Jain
Sarika
S
Stühmer
Thorsten
T
Andrulis
Mindaugas
M
Ungethüm
Ute
U
Kuban
Ralf-Jürgen
RJ
Lorentz
Heike
H
Bommert
Kurt
K
Topp
Max
M
Krämer
Doris
D
Müller-Hermelink
Hans Konrad
HK
Einsele
Hermann
H
Greiner
Axel
A
Bargou
Ralf C
RC
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
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