Targeting HSP90 for cancer therapy

Abstract

Heat-shock proteins (HSPs) are molecular chaperones that regulate protein folding to ensure correct conformation and translocation and to avoid protein aggregation. Heat-shock proteins are increased in many solid tumours and haematological malignancies. Many oncogenic proteins responsible for the transformation of cells to cancerous forms are client proteins of HSP90. Targeting HSP90 with chemical inhibitors would degrade these oncogenic proteins, and thus serve as useful anticancer agents. This review provides an overview of the HSP chaperone machinery and the structure and function of HSP90. We also highlight the key oncogenic proteins that are regulated by HSP90 and describe how inhibition of HSP90 could alter the activity of multiple signalling proteins, receptors and transcriptional factors implicated in carcinogenesis.

Figure 1

The binding of a client protein to HSP90 requires the co-operation of HSP90 with another chaperone, HSP70 and its co-factor HSP40. Both HSP90 and HSP70 chaperones are further linked by an adapter protein called HOP, which binds to both HSP90 and HSP70 through the small helical TPR domains to the C-terminal ends of HSP90 and HSP70. Aha1 is a co-factor that can bind and stimulate activity of HSP90 ATPase. When HSP90 exchanges ADP for ATP, it undergoes conformational change, which dissociates from the HSP70/HSP40/HOP complex, allowing ATP-dependent interaction with other co-chaperones, such as CDC37 and p23, to form a mature complex. It is in this mature state that HSP90 that allows client protein activation following cellular stresses, including phosphorylation of AKT, binding of EGFR to its ligands and ensuring transcription factors, such as HIF-1α and p53, to express genes. Inhibition of ATP-binding through HSP inhibitors prevents client protein maturation and result in degradation of these oncogenic proteins by the proteasome.