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Hsp110/Grp170) in Cancer cells Review The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer Graham Chakafana *,† and Addmore Shonhai * Department of Biochemistry, University of Venda, Private Bag X5050, 0950 Thohoyandou, South Africa * Correspondence: [email protected] (G.C.); [email protected] (A.S.) † Present Address: Department of Medicine, University of Cape Town, Faculty of Health Sciences, Observatory, 7925 Cape Town, South Africa. Abstract: Although cancers account for over 16% of all global deaths annually, at present, no reliable therapies exist for most types of the disease. As protein folding facilitators, heat shock proteins (Hsps) play an important role in cancer development. Not surprisingly, Hsps are among leading anticancer drug targets. Generally, Hsp70s are divided into two main subtypes: canonical Hsp70 (Escherichia coli Hsp70/DnaK homologues) and the non-canonical (Hsp110 and Grp170) members. These two main Hsp70 groups are delineated from each other by distinct structural and functional specifications. Non-canonical Hsp70s are considered as holdase chaperones, while canonical Hsp70s are refoldases. This unique characteristic feature is mirrored by the distinct structural features of these two groups of chaperones. Hsp110/Grp170 members are larger as they possess an extended acidic insertion in their substrate binding domains. While the role of canonical Hsp70s in cancer has received a fair share of attention, the roles of non-canonical Hsp70s in cancer development has received less attention in comparison. In the current review, we discuss the structure-function features of non-canonical Hsp70s members and how these features impact their role in cancer development. We further mapped out their interactome and discussed the prospects of targeting these proteins in cancer therapy. Keywords: Hsp110; Grp170; non-canonical Hsp70; chaperone; cancer Citation: Chakafana, G.; Shonhai, A. The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer. Cells 1. Introduction 2021, 10, 254. https://doi.org/ Cancer accounts for approximately one sixth of total global annual deaths [1]. The 10.3390/cells10020254 most widely used interventions against cancer, such as chemotherapy and radiotherapy, are not always effective due to treatment-induced cellular, genetic and biochemical changes Academic Editor: Boris Margulis that often confer treatment resistance [2]. This, therefore, urgently necessitates the need Received: 16 December 2020 to identify novel anticancer targets. Apart from their role as molecular chaperones, heat Accepted: 26 January 2021 shock proteins (Hsps) play an important role in various cancer signaling pathways such Published: 28 January 2021 as tumorigenesis, carcinogenesis and apoptosis [3,4]. As such, the role of Hsps as cancer biomarkers is increasingly becoming apparent. Publisher’s Note: MDPI stays neutral Several proteins play crucial roles in the key hallmarks of tumorigenesis (Figure1). It with regard to jurisdictional claims in is therefore not surprising that upset of cellular proteostasis is one of the several factors that published maps and institutional affil- could drive tumor cell proliferation and metastasis. Tumor cells therefore rely on robust iations. protein folding machinery to sustain conformational stabilities of the proteins required for their proliferation. As signaling molecules, Hsp members are intimately linked to cancer progression (Figure1). For example, a small Hsp (sHsp), Hsp27 and Hsp70 inhibit release of cytochrome c, caspase 3 and 9 from the mitochondria, thus causing cells to evade Copyright: © 2021 by the authors. apoptosis ([5,6], Figure1). Several studies have indeed demonstrated the inactivation of Licensee MDPI, Basel, Switzerland. the caspase cascade facilitated by Hsp27 binding with caspase 3 and cytochrome c released This article is an open access article from mitochondria [7,8]. Furthermore, Hsp27 also induces resistance to chemotherapy by distributed under the terms and sequestrating cytochrome c upon its release from mitochondria into cytosol [8]. On the conditions of the Creative Commons other hand, Hsp70 blocks apoptosis by binding to Bax to suppress its translocation to mito- Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ chondria [9], thus reducing permeabilization of the mitochondrial membrane, consequently, 4.0/). this inhibits release of mitochondrial apoptogenic molecules, such as cytochrome c [10]. Cells 2021, 10, 254. https://doi.org/10.3390/cells10020254 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 25 Cells 2021, 10, 254 cation to mitochondria [9], thus reducing permeabilization of the mitochondrial mem-2 of 24 brane, consequently, this inhibits release of mitochondrial apoptogenic molecules, such as cytochrome c [10]. 1. Metastasis activation 2. Escape from apoptosis 3. Evasion of anti-growth signals 1. Kinases 70 90 1. p53 70 90 1. PTEN 70 2. ErbB2 70 90 2. Cytc sH 70 2. PML 90 3. MET 3. Ceramide sH 3. TAp73 70 70 90 4. MMP2 60 4. Caspases sH 70 90 4. p53 5. β-caterin 60 5. Survivin 70 90 4. Evasion of senescence 5. Uncontrolled angiogenesis 6. Sustained cell proliferation 1. Telomerase 90 1. HIFα sH 70 90 1. AKT1 60 70 2. p21 60 2. PRKD2 2. IKK 90 3. Myosin 70 90 3. NOS 60 70 3. ERK 90 4. p27 70 90 4. VEGF 70 90 4. EGFR 70 90 5. p53 70 90 5. bFGF sH 5. FGF sH sHsps 60 Hsp60 70 Hsp70 90 Hsp90 FigureFigure 1. 1. TheThe proteomic proteomic landscape landscape of of the the hallmarks hallmarks of of cancer cancer:: The The processes processes of of metastasis, metastasis, uncontrolled uncontrolled angiogenesis, angiogenesis, evasionevasion of of anti anti-growth-growth signals, signals, escape escape from from apoptosis, apoptosis, cell cellproliferation proliferation and evasion and evasion of senescence of senescence are all arecrucial all crucialto tumor to celltumor growth. cell growth. Each of these Each ofprocesses these processes is regulated is regulated by several by proteins several that proteins play thatimportant play important roles in the roles respective in the respectivesignaling pathways. As chaperones, sHsps, Hsp70, Hsp90 and Hsp60 associate with several proteins that regulate cancer signaling signaling pathways. As chaperones, sHsps, Hsp70, Hsp90 and Hsp60 associate with several proteins that regulate cancer pathways. signaling pathways. SinceSince they they are are constantly constantly in in a a state state of of proteotoxic proteotoxic stress, stress, cancer cancer cells cells exploit exploit Hsps Hsps to to protectprotect themselves themselves against thethe toxictoxic effects effects of of aberrant aberrant oncoproteins, oncoproteins, genomic genomic instability, instability, hy- hypoxiapoxia and and acidosis acidosis [11 [,1112,].12 High]. High Hsp Hsp expression expression levels levels are are associated associated with with poor poor prognosis prog- nosisand treatment and treatment resistance resistance in cancer in cancer patients, patients, since Hspssince Hsps protect protect tumor tumor cells from cells therapeuticfrom ther- apeuticstressors stressors such as such radiation as radiation and cytotoxic and cytotoxic chemotherapy chemotherapy [13]. Indeed, [13]. Indeed, overexpression overexpres- of sionHsps of has Hsps been has observed been observed in a wide in a range wide of range cancers, of cancers, including including breast, endometrial,breast, endometrial, ovarian, ovarian,gastric, colon,gastric, lung colon, and lung prostate and cancerprostate [13 cancer–16]. Due[13– to16] their. Due ability to their to overseeability to proteosta- oversee proteostasis,sis, Hsps facilitate Hsps facilitate the folding the folding and maturation and maturation of proteins of proteins involved involved in cancer in cancer signaling sig- nalingpathways pathways (Figure (1Figure). Therefore, 1). Therefore, elevated elevated Hsp levels Hsp are levels often are associated often associated with tumor with pro- tu- morgression progression [4,17–19 [4,17]. In– addition19]. In addition to their proteostaticto their proteostatic functions, functions, some Hsps some are Hsps translocated are trans- to locatedthe cell to surface the cell where surface they where function they as function receptors, as thus receptors, serving thus as conduits serving thatas conduits regulate that sev- regulateeral cancer several signaling cancer pathways signaling including pathways cell including proliferation cell proliferation and invasion and [20]. invasion The presence [20]. Theof Hsps presence on cancer of Hsps cell on surfaces cancer iscell an surfaces aspect that is an warrants aspect that further warrants research, further as it research presents, opportunities for development of novel chemotherapeutic strategies. In addition, Hsps also act as chaperokines that trigger an immune response against oncogenic cells [21]. In a previous study, the Hsp70-derived peptide, TKD, was reported to stimulate natural killer Cells 2021, 10, 254 3 of 24 (NK) cells which then targeted tumor cells harboring Hsp70 on their membranes [22,23]. This further represents a prospective Hsp-mediated anticancer intervention. It has been demonstrated that inhibition of Hsp90 induces degradation of oncogenic proteins [24,25]. Not surprisingly, Hsp90 promotes the conformational maturation of several oncogenic signaling proteins, including steroid receptors such as p53 [26,27] and tyrosine kinases such as ErBb2 ([28], Figure1). Additionally, the expression of some onco- genes in the absence of Hsp70 may result in cell inactivation
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