|
|
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.
 Previous Article | Next Article 
Submitted May 25, 2006
Accepted August 23, 2006
STAT3 and MAPK signaling maintains overexpression of the
heat shock proteins 90 and  in multiple
myeloma cells, which critically contribute to tumor cell
survival
Manik Chatterjee*, Sarika Jain, Thorsten Stuhmer, Mindaugas Andrulis, Ute Ungethum, Ralf-Jurgen Kuban, Heike Lorentz, Kurt Bommert, Max Topp, Doris Kramer, Hans Konrad Muller-Hermelink, Hermann Einsele, Axel Greiner, and Ralf C Bargou
Division of Hematology, University Hospital of Wurzburg, Wurzburg, Germany
Institute of Pathology, University Hospital of Wurzburg, Wurzburg, Germany
Laboratory for Functional Genomics, Charite, University Medicine, Berlin, Germany
* Corresponding author; email: chatterjee_m{at}medizin.uni-wuerzburg.de.
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) 90 and  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 Hsp90 -- 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/ 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 Hsp90 and in MM pathogenesis.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Chatterjee, C. Rancso, T. Stuhmer, N. Eckstein, M. Andrulis, C. Gerecke, H. Lorentz, H.-D. Royer, and R. C. Bargou
The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma
Blood,
April 1, 2008;
111(7):
3714 - 3722.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Mahtouk, D. Hose, J. De Vos, J. Moreaux, M. Jourdan, J. F. Rossi, T. Reme, H. Goldschmidt, and B. Klein
Input of DNA Microarrays to Identify Novel Mechanisms in Multiple Myeloma Biology and Therapeutic Applications
Clin. Cancer Res.,
December 15, 2007;
13(24):
7289 - 7295.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
