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Targeting Heat Shock Protein 27 in Cancer: a Druggable Target for Cancer Treatment?

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Targeting Heat Shock Protein 27 in Cancer: a Druggable Target for Cancer Treatment? cancers Review Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment? Seul-Ki Choi, Heejin Kam, Kye-Young Kim, Suk In Park and Yun-Sil Lee * Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea * Correspondence: [email protected] Received: 3 July 2019; Accepted: 7 August 2019; Published: 16 August 2019 Abstract: Heat shock protein 27 (HSP27), induced by heat shock, environmental, and pathophysiological stressors, is a multi-functional protein that acts as a protein chaperone and an antioxidant. HSP27 plays a significant role in the inhibition of apoptosis and actin cytoskeletal remodeling. HSP27 is upregulated in many cancers and is associated with a poor prognosis, as well as treatment resistance, whereby cells are protected from therapeutic agents that normally induce apoptosis. This review highlights the most recent findings and role of HSP27 in cancer, as well as the strategies for using HSP27 inhibitors for therapeutic purposes. Keywords: heat shock protein 27; HSP27 inhibitor; anti-cancer drugs; resistance 1. Introduction The heat shock protein (HSP) is a protein family produced in cells by stressors, such as hypoxia, hyperoxia, UV light exposure, viral agents, and nutritional deficiencies. Its primary role is to maintain cellular homeostasis, promoting cell survival in lethal conditions. It associates with major regulatory proteins, such as transcriptional factors, protein kinases, and hormone receptors [1]. HSPs protect cells by acting as molecular chaperones which correct misfolded proteins. There are many types of HSPs, and their functions vary slightly. Although there are a few ways to classify HSPs, one way is to categorize them by their molecular weight. For example, the HSP27 molecule is 27 kDa in size. Using their molecular weights, mammalian HSPs can be classified into six families: HSP100, HSP90, HSP70, HSP60, HSP40, and small HSPs (sHSP, 15 to 30 kDa) [2]. HSP27 is a type of small Heat Shock Protein (sHSP). The mammalian sHSP family, also known as the HSPB family, contains ten members: HSPB1 to HSPB10, HSP27/HSPB1, MKBP (Myotonic dystrophy protein kinase-binding protein)/HSPB2, HSPB3, αA-crystallin/HSPB4, αB-crystallin/HSPB5, HSP20/HSPB6, cvHSP (cardiovascular heat shock protein)/HSPB7, HSP22/HSPB8, HSPB9, and ODF1 (outer dense fiber protein)/HSPB10 [3]. HSP27 is encoded on the HSPB1 gene and belongs to a family of ATP-independent chaperones. HSP27 is a single copy gene covering 2.2 kb transcripts organized into three exons encoding a 205 amino acid protein. The mechanism of its substrates and chaperone function have not been fully studied compared to other large HSPs. HSP27 is reported to be involved in cell resistance to stress factors and heat shock. However, the function of HSP27 is hijacked during disease, and HSP27 helps to promote disease, rather than appropriately regulate cell homeostasis. HSP27 is present in both the cytoplasm and nucleus. Heat shock and exposure to various stressful conditions can cause it to localize to the nucleus. It was shown that the overexpression of HSP27 promoted recovery from the aggregation of heat-induced nuclear-protein [4], suggesting that HSP27 was partly responsible for subsequent cell survival. Therefore, HSP27 plays a fundamental role in cell physiology in various disease states, including cancer (Figure1). Cancers 2019, 11, 1195; doi:10.3390/cancers11081195 www.mdpi.com/journal/cancers Cancers 2019, 11, 1195 2 of 17 Cancers 2019, 11, x 2 of 17 Figure 1. Figure 1. MajorMajor rolesroles ofof heatheat shockshock proteinprotein 2727 (HSP27).(HSP27). HSP27HSP27 hashas importantimportant functions,functions, includingincluding protein folding regulation by chaperone activity, immune response, cancer promotion, inducing protein folding regulation by chaperone activity, immune response, cancer promotion, inducing resistance to anticancer drugs, aging, biomarkers of several diseases, aggravation of neurodegenerative resistance to anticancer drugs, aging, biomarkers of several diseases, aggravation of disease, development, and differentiation [5–8]. neurodegenerative disease, development, and differentiation [5–8]. In the following section, we present an overview of HSP27 and discuss the highly complex patterns In the following section, we present an overview of HSP27 and discuss the highly complex of HSP27 phosphorylation and oligomerization related to its function. We also examine inhibitors patterns of HSP27 phosphorylation and oligomerization related to its function. We also examine targeted to HSP27 as cancer treatment strategies. inhibitors targeted to HSP27 as cancer treatment strategies. 2. Structure of HSP27 2. Structure of HSP27 Small HSPs are the most diverse in structure among the molecular chaperones. HSP27 contains a highlySmall conserved HSPs areα-crystallin the most domain.diverse in [4 ].structure In humans, among the theα-crystallin molecular domain chaperones. plays aHSP27 crucial contains role in dimera highly formation conserved [9]. α The-crystallin structure domain. of α-crystallin [4]. In humans, is dynamic the and α-crystallin is affected domain by rapid plays subunit a crucial exchange role underin dimer stressful formation conditions [9]. The [10 ].structure HSP27 actsof α as-crystallin a chaperone is dynamic to form multimericand is affected complexes by rapid in cells subunit and toexchange stabilize under denatured stressful or aggregatedconditions proteins[10]. HSP27 and ac returnts as a them chaperone to their to original form multimeric form [11]. complexes Since the oligomericin cells and conformation to stabilize denatured of HSP27 or and aggregated the monomeric proteins form and occurreturn dynamically, them to their furtheroriginal research form [11]. is neededSince the to determineoligomeric whetherconformation oligomers of HSP27 or monomers and the are monomeric required forform protein occur homeostasis dynamically, and further what theyresearch do. is needed to determine whether oligomers or monomers are required for protein homeostasisX-ray analysis and what has revealedthey do. the crystallin domain of HSP27; however, the entire molecular structure is stillX-ray unknown analysis because has revealed it was di ffithculte crystallin to obtain domain a stable of crystal HSP27; of HSP27’s however, oligomeric the entire protein molecular [12]. Therefore,structure is by still using unknown Psipred because [13], a secondary it was difficult structure to helixobtain and a stable strand crystal was deduced of HSP27’s from oligomeric the amino acidprotein sequence [12]. Therefore, of HSP27. by A using complete Psipred tertiary [13], structurea secondary has structure not yet been helix obtained and strand and was may deduced not be obtainablefrom the amino due to acid the sequence coil being of too HSP27. flexible. A complete HSP27 has tertiary a poorly structure conserved, has not disorganized yet been obtained N-terminal and andmay a not highly be obtainable flexible, variable due to the C-terminal. coil being HSP27too flex isible. likely HSP27 to change has a poorly its structure conserved, depending disorganized on the conditions,N-terminal such and as a thehighly pH and flexible, temperature variable [14 ].C-terminal. It might be possibleHSP27 is to obtainlikely ato tertiary change structure its structure under verydepending specific on conditions. the conditions, HSP27 such contains as the a poorly-conserved pH and temperature WDPF [14]. domain It might region, be possible a highly-conserved to obtain a αtertiary-crystallin structure domain under region very with specificβ-sheets, conditions. a partially HSP27 conserved contains PSRLFDQXFGEXLL a poorly-conserved sequence, WDPF domain and a flexibleregion, C-terminal.a highly-conserved The WDPF α domain-crystallin name domain was derived region fromwith the β-sheets, amino acid a partially residues itconserved contains, includingPSRLFDQXFGEXLL W (tryptophan), sequence, D (aspartic and a flexible acid), C-termin P (proline),al. The and WDPF F (phenylalanine). domain name was The derivedα-crystallin from structurethe amino is acid important residues for oligomerizationit contains, including and solubility W (tryptophan), [15]. HSP27 D (aspartic is an ATP-independent acid), P (proline), molecular and F chaperone(phenylalanine). involved The in α protein-crystallin folding-refolding structure is important machinery fo [r16 oligomerization]. Several studies and have solubility shown that[15]. constitutivelyHSP27 is an ATP-independent expressed HSP27 molecular has irrelevant chaperone cellular involved functions in protein that can folding-refolding lead to interactwith machinery many other[16]. Several protein studies partners have [17 ].shown Therefore, that constitutively it is crucial to expressed understand HSP27 the structurehas irrelevant of HSP27 cellular to graspfunctions the structure–functionthat can lead to interact relationship, with many including other protein modulation partners of the [17]. activity Therefore, and half-livesit is crucial of to many understand crucial clientthe structure polypeptides of HSP27 [18]. Oneto grasp of the the major structure–func challenges intion HSP27 relationship, research isincluding determining modulation the factors of that the aactivityffect its and activity half-lives level, suchof many as the crucial extent client of oligomerization, polypeptides [18]. the One interaction of the major with protein challenges partners, in HSP27 etc., whichresearch may is leaddetermining
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