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Blood, 15 January 2007, Vol. 109, No. 2, pp. 720-728.
Prepublished online as a Blood First Edition Paper on September 26, 2006; DOI 10.1182/blood-2006-05-024372.
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NEOPLASIA
STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90 and ß in multiple myeloma cells, which critically contribute to tumor-cell survival
Manik Chatterjee1,2,,
Sarika Jain1,2,
Thorsten Stühmer1,
Mindaugas Andrulis3,
Ute Ungethüm4,
Ralf-Jürgen Kuban4,
Heike Lorentz1,
Kurt Bommert1,
Max Topp1,
Doris Krämer1,
Hans Konrad Müller-Hermelink3,
Hermann Einsele1,
Axel Greiner3, and
Ralf C. Bargou1
1 Department of Internal Medicine II, Division of Hematology, University Hospital of Würzburg, Germany;
2 Robert Rössle Cancer Clinic at the Max Delbrück Center for Molecular Medicine, Berlin, Germany;
3 Institute of Pathology, University Hospital of Würzburg, Germany; and
4 Laboratory for Functional Genomics, Charité, University Medicine Berlin, Germany
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) 90 and ß 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 Hsp90ß—unlike knockdown of Hsp90—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 Hsp90/ß 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 Hsp90 and ß in MM pathogenesis.
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