Cleavage Of Hsp90 Beta Induced By Histone Deacetylase Inhibitor And Proteasome Inhibitor Modulates Cell Growth And Apoptosis

HSP90, one of the molecular chaperones, contributes to protein stability in most living organisms. Previously, we found cleavage of HSP90 by caspase 10 in response to treatment with histone deacetylase inhibitor or proteasome inhibitor in leukemic cell lines. In this study, we investigated this phenomenon in various cell lines and found that HSP90 was cleaved by treatment with SAHA or MG132 in 6 out of 16 solid tumor cell lines. To further investigate the effects of HSP90 cleavage on cells, we introduced mutations to the potential cleavage sites of HSP90 beta and found that the 294th aspartic acid residue of the protein was mainly cleaved. In the K562 and Mia-PaCa-2 cell lines expressing HSP90 beta D294A, the cleavage of HSP90 by the treatment with SAHA or MG132 was reduced compared with the K562 and Mia-PaCa-2 cell lines expressing HSP90 beta WT. Accordingly, cell growth and survival were enhanced by HSP90 beta D294A expression. Therefore, we suggest that HSP90 cleavage widely occurs in several cell lines, and cleavage of HSP90 may have a potential for one of the mechanisms involved in the anti-tumor effects of known drugs and novel anti-tumor drug candidates.