The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer

Abstract

Prostate cancer (PCa) is one of the most common cancer types in men worldwide. Heat shock proteins (HSPs) are molecular chaperones that are widely implicated in the pathogenesis, diagnosis, prognosis, and treatment of many cancers. The role of HSPs in PCa is complex and their expression has been linked to the progression and aggressiveness of the tumor. Prominent chaperones, including HSP90 and HSP70, are involved in the folding and trafficking of critical cancer-related proteins. Other members of HSPs, including HSP27 and HSP60, have been considered as promising biomarkers, similar to prostate-specific membrane antigen (PSMA), for PCa screening in order to evaluate and monitor the progression or recurrence of the disease. Moreover, expression level of chaperones like clusterin has been shown to correlate directly with the prostate tumor grade. Hence, targeting HSPs in PCa has been suggested as a promising strategy for cancer therapy. In the current review, we discuss the functions as well as the role of HSPs in PCa progression and further evaluate the approach of inhibiting HSPs as a cancer treatment strategy.

Keywords: HSPs inhibitors; biomarkers; heat shock proteins (HSPs); molecular chaperones; prostate cancer; therapeutic resistance.

Figure 1

Induction of HSR by HSF1. Various factors including environmental, non-stress and pathological conditions can trigger HSP expression via HSF1 pathway. In non-activated state, HSF1 is sequestered in the cytoplasm due to its binding to chaperone complex including HSP70 and HSP90, thus prevented from performing its transcriptional activity. Upon activation, the chaperone complex dissociates and HSF1 is liberated, homotrimerizes and translocated to the nucleus. In the nucleus, the HSF1 homotrimer binds to the heat shock elements (HSEs) that are located upstream to heat shock gene promotors to initiate the transcription of its target genes including HSP genes.

Figure 2

Domain architecture of common chaperones involved in PCa. From top to bottom, human HSPs including HSP90α/β, HSP70, HSP60, HSP27, are displayed relative to their relative length where the number of amino acids constituting each chaperone is written as superscripts in their C-terminals. HSPs have N- and C-terminal domains in addition to middle domain like HSP90 and HSP70 while linear representation of human HSP60 domains is still unclear due to its oligomerization and complex association with HSP10. HSP27 has a middle highly conserved α-crystalline domain. Phosphorylation sites of HSP27 are designated as yellow spheres representing either phosphorylated serine or threonine amino acid residues. Human clusterin (CLU) exists initially as polypeptide precursor which undergoes proteolytic cleavage of its first 22 amino acid secretory signal in addition to its cleavage at Arg227–Ser228 to yield two chains; namely α and β chains. The two chains are arranged in anti-parallel orientation to constitute a heterodimeric molecule. Pink boxes represent cysteine-rich centers that are linked by five disulfide bridges. Yellow ovals point to predicted amphipathic α-helices while green tetragonal stars refer to the N-glycosylation sites.

Figure 3

HSPs regulate AR signaling. A complex of chaperones including HSP90 associates with the AR to expedite and maintain its high affinity binding conformation, thus allowing for DHT interaction. As a consequence, the AR forms a dimer and the chaperone complex dissociates. Thereafter, HSP27 binds to the AR homodimer enabling its nuclear translocation, subsequent binding to the ARE, and activation of transcription of AR-dependent genes.

Figure 4

Common small inhibitors of HSP90.