Traditional and Novel Mechanisms of Heat Shock Protein 90 (HSP90) Inhibition in Cancer Chemotherapy Including HSP90 Cleavage

Abstract

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the growth and survival of cancer cells. HSP90 inhibitors mainly bind to the ATP binding site of HSP90 and inhibit HSP90 activity, and these inhibitors can be distinguished as ansamycin and non-ansamycin depending on the structure. In addition, the histone deacetylase inhibitors inhibit the activity of HSP90 through acetylation of HSP90. These HSP90 inhibitors have undergone or are undergoing clinical trials for the treatment of cancer. On the other hand, recent studies have reported that various reagents induce cleavage of HSP90, resulting in reduced HSP90 client proteins and growth suppression in cancer cells. Cleavage of HSP90 can be divided into enzymatic cleavage and non-enzymatic cleavage. Therefore, reagents inducing cleavage of HSP90 can be classified as another class of HSP90 inhibitors. We discuss that the cleavage of HSP90 can be another mechanism in the cancer treatment by HSP90 inhibition.

Keywords: ATP binding; Acetylation; Anti-cancer therapy; HSP90 cleavage; HSP90 inhibitors.

Fig. 1.

Diagram of HSP90 inhibitor-mediated tumor cell suppression. HSP90 inhibitors are known to inhibit the binding of ATP, block binding to co-chaperones and regulate acetylation to inhibit the activity of HSP90. In addition, the cleavage of HSP90 discussed in this paper appears to suppress the activity of HSP90. Inhibition of HSP90 by HSP90 inhibitors reduces chaperone activity and inhibits growth and survival of tumor cells through degradation of the HSP90 client proteins.