Heat Shock Protein 70 and 90 Family in Prostate Cancer

Abstract

Prostate cancer (PCa) is the second most frequent cancer that affects aging men worldwide. However, its exact pathogenesis has not been fully elucidated. The heat shock protein (HSP) family has cell-protective properties that may promote tumor growth and protect cancer cells from death. On a cellular level, HSP molecules have a strong relationship with multiple important biological processes, such as cell differentiation, epithelial-mesenchymal transition (EMT), and fibrosis. Because of the facilitation of HSP family molecules on tumorigenesis, a number of agents and inhibitors are being developed with potent antitumor effects whose target site is the critical structure of HSP molecules. Among all target molecules, HSP70 family and HSP90 are two groups that have been well studied, and therefore, the development of their inhibitors makes great progress. Only a small number of agents, however, have been clinically tested in recruited patients. As a result, more clinical studies are warranted for the establishment of the relationship between the HSP70 family, alongside the HSP90 molecule, and prostate cancer treatment.

Keywords: HSP70s; HSP90s; heat shock protein; prostate cancer.

Figure 1

Schematic illustration of the influencing factors of HSPs alteration and its relationship with PCa pathogenesis: External stresses such as hyperthermia, hypoxia and infectious agents stimulate the expression of HSPs, which further affects protein folding, pyroptosis and apoptosis, autophagy, EMT, and DNA repair and ultimately triggers the pathophysiological process of prostate cancer.

Figure 2

Structure of HSP70s and HSP90s (a) HSP70s consist of two main domains, namely, the N-terminal nucleotide-binding domain (NBD) responsible for ATPase activity and the C-terminal substrate-binding domain (SBD) required for peptide binding. The linker connects two domains. The N-terminal NBD provides ATP/ADP pockets for ATP binding. SBD is further divided into two subdomains (SBDα and SBDβ) and followed by a C-terminal ending with an EEVD motif. The main function of SBDβ is to bind substrate peptides, which is the critical step of substrate folding. (b) HSP90s monomers are composed of an amino terminal domain (NTD), an intermediate domain (MD), and a C-terminal domain (CTD). CTD contains a C-terminal met-Glu-Glu-Val-Asp (MEEVD) motif. The three domains function differently: the NTD mediates binding to ATP, the MD is involved in ATP hydrolysis and HSP90 binding to client proteins and the CTD is responsible for the formation of dimers.