Proteasome inhibitor-induced cleavage of HSP90 is mediated by ROS generation and caspase 10-activation in human leukemic cells.

Heat shock protein 90 (HSP90) is a molecular chaperone that supports the stability of client proteins. The proteasome is one of the targets for cancer therapy, and studies are underway to use proteasome inhibitors as anti-cancer drugs. In this study, we found that HSP90 was cleaved to a 55kDa protein after treatment with proteasome inhibitors including MG132 in leukemia cells but was not cleaved in other tissue-derived cells. HSP90 has two major isoforms (HSP90α and HSP90β), and both were cleaved by MG132 treatment. MG132 treatment also induced a decrease in HSP90 client proteins. MG132 treatment generated ROS, and the cleavage of HSP90 was blocked by a ROS scavenger, N-acetylcysteine (NAC). MG132 activated several caspases, and the activation was reduced by pretreatment with NAC. Based on an inhibitor study, the cleavage of HSP90 induced by MG132 was dependent on caspase 10 activation. Furthermore, active recombinant caspase 10 induced HSP90 cleavage in vitro. MG132 upregulated VDUP-1 expression and reduced the GSH levels implying that the regulation of redox-related proteins is involved. Taken all together, our results suggest that the cleavage of HSP90 by MG132 treatment is mediated by ROS generation and caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in the anti-cancer effects of proteasome inhibitors.