Role and Regulation of Heat Shock Proteins 90alpha and 90beta in Multiple Myeloma.

The combined blockade of the IL-6R/STAT3 and the MAPK signaling pathways has been shown to inhibit bone marrow microenvironment-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. Interestingly, in situ overexpression of both Hsp90 proteins was observed in the majority of MM, but not in MGUS or in normal plasma cells. SiRNA-mediated knockdown of Hsp90 or treatment with the novel Hsp90 inhibitor 17-DMAG attenuated the levels of phospho-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 bone marrow microenvironment 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. Our results emphasize a role for Hsp90alpha and Hsp90beta in MM pathogenesis.