Heat Shock Proteins in Benign Prostatic Hyperplasia and Prostate Cancer

Abstract

Two out of three diseases of the prostate gland affect aging men worldwide. Benign prostatic hyperplasia (BPH) is a noncancerous enlargement affecting millions of men. Prostate cancer (PCa) in turn is the second leading cause of cancer death. The factors influencing the occurrence of BPH and PCa are different; however, in the course of these two diseases, the overexpression of heat shock proteins is observed. Heat shock proteins (HSPs), chaperone proteins, are known to be one of the main proteins playing a role in maintaining cell homeostasis. HSPs take part in the process of the proper folding of newly formed proteins, and participate in the renaturation of damaged proteins. In addition, they are involved in the transport of specific proteins to the appropriate cell organelles and directing damaged proteins to proteasomes or lysosomes. Their function is to protect the proteins against degradation factors that are produced during cellular stress. HSPs are also involved in modulating the immune response and the process of apoptosis. One well-known factor affecting HSPs is the androgen receptor (AR)—a main player involved in the development of BPH and the progression of prostate cancer. HSPs play a cytoprotective role and determine the survival of cancer cells. These chaperones are often upregulated in malignancies and play an indispensable role in tumor progression. Therefore, HSPs are considered as one of the therapeutic targets in anti-cancer therapies. In this review article, we discuss the role of different HSPs in prostate diseases, and their potential as therapeutic targets.

The Role of Heat Shock Protein 70 Subfamily in the Hyperplastic Prostate: From Molecular Mechanisms to Therapeutic Opportunities

“…Early in the 1980s, comparably higher nuclear AR levels were observed in the hyperplastic prostate [36,37]. As a member of the nuclear hormone receptor superfamily, AR has only been detected in the nucleus of prostate cells, which was confirmed by data on both normal prostate tissues and hyperplastic prostate tissues [16]. Recently, AR has been found to modulate the cellular growth of both stromal and epithelial cells, as well as the EMT process [9,38].…”

“…Mechanistically, molecular inhibitors binding to C-terminal SBD are capable of disrupting the association of HSP70s with their co-chaperone HSP40 and other client proteins, while those targeting the N-terminal ATPbinding domain are able to disrupt the ATPase activity of HSP70s, thereby both inhibitors can induce cell apoptosis and reduce the volume of target organs. All these molecular inhibitors have been well studied in many cancers, including prostate cancer [16,125,126], but most of them have not been successfully developed for commercial use, with only MKT-077 being clinically tested.…”

“…The HSP family is evolutionarily conserved and ubiquitously expressed in all organisms and various cellular compartments [15]. Based on molecular weight, HSPs are commonly classified into six subfamilies: HSPH (HSP110), HSPC (HSP90), HSPA (HSP70), DNAJ (HSP40), HSPB (small HSPs (sHSPs)), as well as chaperonin families: HSPD/E (HSP60/HSP10) and CCT (cytosolic chaperonin TCP1 ring complex (TRIC)) [16]. The members of the HSP70 subfamily weigh 68-78 kDa and primarily include HSP70, glucose-regulated protein 78 (GRP78) and mortalin [17].…”

“…The members of the HSP70 subfamily weigh 68-78 kDa and primarily include HSP70, glucose-regulated protein 78 (GRP78) and mortalin [17]. It has been noted that HSP70s modulate multiple biological processes associated with the development of BPH, such as cell survival and proliferation, cell apoptosis and the androgen receptor (AR) pathway [16,18,19]. These molecules are also involved in EMT and OS, acting as key regulators in two processes [18,20].…”

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

“…At the genetic level, two-fold increases in the AR mRNA expression levels have been reported in the CRPC tumors [ 16 ]. The AR overexpression can additionally occur through the enhanced stabilization of AR mRNA or proteins, or through increased transduction rates mediated by heat-shock proteins (HSPs), with HSP40 and HSP70 having been shown to bind the AR NTD and to then interact with the AR LBD, thereby contributing to its overexpression [ 17 , 18 ].…”