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Review
. 2024 Feb 1;16(3):638.
doi: 10.3390/cancers16030638.

The Interplay between Heat Shock Proteins and Cancer Pathogenesis: A Novel Strategy for Cancer Therapeutics

Prathap Somu  1 , Sonali Mohanty  2 , Nagaraj Basavegowda  3 , Akhilesh Kumar Yadav  4   5 , Subhankar Paul  2 , Kwang-Hyun Baek  3
Affiliations
Review

The Interplay between Heat Shock Proteins and Cancer Pathogenesis: A Novel Strategy for Cancer Therapeutics

Prathap Somu et al. Cancers (Basel). .

Abstract

Heat shock proteins (HSPs) are developmentally conserved families of protein found in both prokaryotic and eukaryotic organisms. HSPs are engaged in a diverse range of physiological processes, including molecular chaperone activity to assist the initial protein folding or promote the unfolding and refolding of misfolded intermediates to acquire the normal or native conformation and its translocation and prevent protein aggregation as well as in immunity, apoptosis, and autophagy. These molecular chaperonins are classified into various families according to their molecular size or weight, encompassing small HSPs (e.g., HSP10 and HSP27), HSP40, HSP60, HSP70, HSP90, and the category of large HSPs that include HSP100 and ClpB proteins. The overexpression of HSPs is induced to counteract cell stress at elevated levels in a variety of solid tumors, including anticancer chemotherapy, and is closely related to a worse prognosis and therapeutic resistance to cancer cells. HSPs are also involved in anti-apoptotic properties and are associated with processes of cancer progression and development, such as metastasis, invasion, and cell proliferation. This review outlines the previously mentioned HSPs and their significant involvement in diverse mechanisms of tumor advancement and metastasis, as well as their contribution to identifying potential targets for therapeutic interventions.

Keywords: HSP inhibitors; apoptosis; cancer; chemosensitizing agent; heat shock proteins; molecular chaperones.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 3
Figure 3
Strategies targeting cancer cells based on HSP27 inhibition. (A) Small molecules, such as quercetin and RP101 (brivudine), can directly bind to HSP27 and suppress its function. (B) Peptide aptamers such as PA11 and PA50 can specifically bind to HSP27, inhibiting HSP27 dimerization or oligomerization, thereby disabling its function. (C) The final strategy applies Apatorsen (OGX-427), an antisense oligonucleotide that binds to HSP27 mRNA and blocks HSP27 translation, thereby HSP 27 protein production inhibited. Consequently, the amount of HSP27 is reduced, causing cell death, which protects the cell through its anti-apoptotic activity. Reprinted (adapted) with permission from Ref. [61]. Copyright 2013, Elsevier.
Figure 4
Figure 4
(A) Structures of HSP70 inhibitors. (B) Schematic diagram of the domain architecture of HSP70 and the possible sites targeted by various inhibitors. Reprinted (adapted) with permission from Ref. [135]. Copyright 2015, Springer Nature.
Figure 1
Figure 1
Role of HSP in biochemical functions of cells. (A) Chaperone activity: misfolded proteins that accumulate in the cytosol bind to HSPs to maintain homeostatic balance (A.1). For example, the HSP70/HSP40 complex guides the degradation of misfolded proteins into short peptides via proteasome (A.2). (B) Role of HSP in the autophagy pathway: the autophagy cycle begins by binding HSP70 to the protein (B.1). Regulation of Atg13, FIP200, and ULK1 complex induced by HSPs (B.2). The initiation of the VPS4, Atg14, and Beclin1 complexes is regulated by HSPs (B.3). Ultimately, phagosomes are formed using phagosomal markers (B.4). Finally, autophagosomes or amphisomes fuse with lysosomes (B.5). (C) Role of HSP in different apoptotic pathways: HSPs help in modulating pro-apoptotic signals through FasL at the mitochondrial and post-mitochondrial levels. HSP70 and HSP27 appear to suppress the release of mitochondrial pro-apoptotic proteins by activating Bax and tBid (truncated Bid), respectively (C.1). HSP27, HSP70, and HSP90 can interact with and recruit Apaf-1 (apoptosis protease-activating factor 1) by directly sequestering cytochrome C to prevent apoptosome oligomerization and activation (C.2). HSP27 can also inhibit apoptosis via inactivation of caspase 3 and ASK (apoptosis signal-regulated kinase) (C.3). Furthermore, HSP60 and TLR-4 interactions mediate the NF-kappaB (NF-κB) signaling pathway, resulting in the activation of caspases 3, 6, and 7 and DNase (C.4). Reprinted (adapted) with permission from Ref. [44]. Copyright 2019, Future Medicine Ltd., London, UK.
Figure 2
Figure 2
(A) Structure of HSP27 and its putative phosphorylation sites. (B) Schematic representation showing the two different conformational states of HSP27 induced by phosphorylation, that is, large oligomers when unphosphorylated and small oligomers when phosphorylation is catalyzed by MAPKAPK 2/3 kinase at specific serine residues of HSP27. These conformational, structural, and functional changes actively contribute to the maintenance of cellular proteostasis [49].
Figure 5
Figure 5
The chaperone, HSP90, undergoes multiple conformational states in the absence of nucleotides or other factors. ATP binding and hydrolysis shift conformational equilibrium by lowering the energy barrier between specific conformations, thus providing a conformational cycle for HSP90 [165]. ATP binds to the undimerized NTD (open state) of HSP90 and leads to N-terminal dimerization caused by the “lid” segment (red) repositioning. The subsequent structural rearrangement establishes a (closed and twisted) conformation of HSP90, which is suitable for ATP hydrolysis. The co-chaperone AHA1 increases HSP90 ATPase 1 activity by promoting conformational changes required to achieve ATPase competence. In the absence of AHA1, it was very difficult for HSP90 to achieve ATPase-competent conformation (dotted arrow). A number of co-chaperones, including Sti1p (p60HOP), Cdc37 homolog (cell division cycle 37), and N-domain-binding HSP90 inhibitors, prevent dimerization of the N-terminal domain. PTGES3 (prostaglandin E synthase 3 cytosolic, so-called p23 protein) deregulates the ATPase cycle and stabilizes its closed conformation. Reprinted (adapted) with permission from Ref. [163]. Copyright 2010, Springer Nature.
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Grants and funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2021R1F1A1060297).