Characterization of novel isoform-specific HSP90 inhibitors

Abstract

90kDa heat shock proteins (HSP90) belong to a family of molecular chaperones involved in the maintenance of dysregulated proteins. Therefore, HSP90 is a promising target in cancer drug research. Classical HSP90 inhibitors activate the heat shock response (HSR), mechanism that enables the cell to respond to a wide range of stress conditions. The HSR is counterproductive in the treatment of cancer as heat shock proteins (HSPs) are induced. The current HSR model proposes the formation of HSP90-HSF1 complex that is disrupted by stress stimuli. Recent studies have shown that HSF2 can also form a complex with HSP90, which suggests a role modulating the HSR. The aim of this study was to characterize 9 novel isoform-specific HSP90 inhibitors by whether they induced the HSR in U2OS wild type cells and HSF knock-out cells (HSF KO), after 18 h treatments and immunoblot analysis. Additionally, sensitivity of the cell lines to the compounds was characterized with cell viability and cytotoxicity assay. Results show that N-terminal inhibitors induce a strong HSR on wild type cells and HSF2 KO cells at low and high doses whereas GRP94 and C-terminal inhibitors only at high doses. It is also shown that HSF1 KO cells are more sensitive to specific inhibitors than the rest of the cell lines. Overall, selective suppression of HSP90 isoforms may enhance the potential of novel cancer therapies. This study also reflects the importance of understanding how the HSR can be modulated with novel cancer drugs to improve cancer treatments.