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Molecular Chaperones: Cancer and Cell Death
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Molecular Chaperones: Cancer and Cell Death

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 115774

Special Issue Editor

Prof. Boris Margulis

E-Mail Website
Guest Editor
Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, 194064 St. Petersburg, Russia
Interests: molecular chaperones; protein–protein interactions; molecular targets in anticancer therapy; propagation of neurodegenerative pathologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The analysis of systems maintaining cell proteotostasis and based on molecular chaperones shows that these mechanisms are closely associated with the molecular systems controlling cell survival, growth, and proliferation. Moreover, chaperones are essential to the response to a variety of pathogenic, as well as therapeutic, factors. It is also important to note that elevating the chaperone content in cells increases their protection against harmful agents. Cancer cells of many types over-express chaperones to fight against well-known stressors, such as oxidative stress and hypoxia, as well as against anti-tumor medicines, particularly drugs inducing apoptosis. Generally, chaperones are activated due to transcriptional signals controlling the behavior of a cell in changing surroundings, while, functionally, the chaperones are involved in the most important processes, defining a compromise between cell death, life, and growth and being implicated in apoptosis, autophagy, and protein quality control. Therefore, targeting molecular chaperones may cause fluctuations in different signaling systems, and such inhibition has been shown to result in tumor delay or death. Strikingly, some chaperones occurring exogenously play a pivotal role in the induction of the immunological response to tumors, and this effect is employed in the protocols of immunotherapy of hard tumors.

The goal of this Special Issue is to broadly present the current knowledge on the role of chaperones in the process of cancer progression and cell death/survival.

We look forward to your contributions.

Prof. Boris Margulis
Guest Editor

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Keywords

  • chaperones
  • cancer
  • heat shock proteins
  • immunotherapy

Published Papers (20 papers)

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Research

Jump to: Review

14 pages, 1952 KiB  
Article
Modulation of Plasma Membrane Composition and Microdomain Organization Impairs Heat Shock Protein Expression in B16-F10 Mouse Melanoma Cells
by Tim Crul, Balint Csoboz, Imre Gombos, Annamaria Marton, Maria Peter, Gabor Balogh, Csaba Vizler, Lajos Szente and Laszlo Vigh
Cells 2020, 9(4), 951; https://doi.org/10.3390/cells9040951 - 12 Apr 2020
Cited by 7 | Viewed by 3492
Abstract
The heat shock response (HSR) regulates induction of stress/heat shock proteins (HSPs) to preserve proteostasis during cellular stress. Earlier, our group established that the plasma membrane (PM) acts as a sensor and regulator of HSR through changes in its microdomain organization. PM microdomains [...] Read more.
The heat shock response (HSR) regulates induction of stress/heat shock proteins (HSPs) to preserve proteostasis during cellular stress. Earlier, our group established that the plasma membrane (PM) acts as a sensor and regulator of HSR through changes in its microdomain organization. PM microdomains such as lipid rafts, dynamic nanoscale assemblies enriched in cholesterol and sphingomyelin, and caveolae, cholesterol-rich PM invaginations, constitute clustering platforms for proteins functional in signaling cascades. Here, we aimed to compare the effect of cyclodextrin (MβCD)- and nystatin-induced cholesterol modulations on stress-activated expression of the representative HSPs, HSP70, and HSP25 in mouse B16-F10 melanoma cells. Depletion of cholesterol levels with MβCD impaired the heat-inducibility of both HSP70 and HSP25. Sequestration of cholesterol with nystatin impaired the heat-inducibility of HSP25 but not of HSP70. Imaging fluorescent correlation spectroscopy marked a modulated lateral diffusion constant of fluorescently labelled cholesterol in PM during cholesterol deprived conditions. Lipidomics analysis upon MβCD treatment revealed, next to cholesterol reductions, decreased lysophosphatidylcholine and phosphatidic acid levels. These data not only highlight the involvement of PM integrity in HSR but also suggest that altered dynamics of specific cholesterol pools could represent a mechanism to fine tune HSP expression. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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23 pages, 2794 KiB  
Article
Overexpression of GRP78/BiP in P-Glycoprotein-Positive L1210 Cells is Responsible for Altered Response of Cells to Tunicamycin as a Stressor of the Endoplasmic Reticulum
by Mário Šereš, Lucia Pavlíková, Viera Boháčová, Tomáš Kyca, Ivana Borovská, Boris Lakatoš, Albert Breier and Zdena Sulová
Cells 2020, 9(4), 890; https://doi.org/10.3390/cells9040890 - 06 Apr 2020
Cited by 9 | Viewed by 4906
Abstract
P-glycoprotein (P-gp, ABCB1 member of the ABC (ATP-binding cassette) transporter family) localized in leukemia cell plasma membranes is known to reduce cell sensitivity to a large but well-defined group of chemicals known as P-gp substrates. However, we found previously that P-gp-positive sublines of [...] Read more.
P-glycoprotein (P-gp, ABCB1 member of the ABC (ATP-binding cassette) transporter family) localized in leukemia cell plasma membranes is known to reduce cell sensitivity to a large but well-defined group of chemicals known as P-gp substrates. However, we found previously that P-gp-positive sublines of L1210 murine leukemia cells (R and T) but not parental P-gp-negative parental cells (S) are resistant to the endoplasmic reticulum (ER) stressor tunicamycin (an N-glycosylation inhibitor). Here, we elucidated the mechanism of tunicamycin resistance in P-gp-positive cells. We found that tunicamycin at a sublethal concentration of 0.1 µM induced retention of the cells in the G1 phase of the cell cycle only in the P-gp negative variant of L1210 cells. P-gp-positive L1210 cell variants had higher expression of the ER stress chaperone GRP78/BiP compared to that of P-gp-negative cells, in which tunicamycin induced larger upregulation of CHOP (C/EBP homologous protein). Transfection of the sensitive P-gp-negative cells with plasmids containing GRP78/BiP antagonized tunicamycin-induced CHOP expression and reduced tunicamycin-induced arrest of cells in the G1 phase of the cell cycle. Taken together, these data suggest that the resistance of P-gp-positive cells to tunicamycin is due to increased levels of GRP78/BiP, which is overexpressed in both resistant variants of L1210 cells. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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24 pages, 4487 KiB  
Article
Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells
by Takanori Eguchi, Chiharu Sogawa, Kisho Ono, Masaki Matsumoto, Manh Tien Tran, Yuka Okusha, Benjamin J. Lang, Kuniaki Okamoto and Stuart K. Calderwood
Cells 2020, 9(3), 755; https://doi.org/10.3390/cells9030755 - 19 Mar 2020
Cited by 49 | Viewed by 5988
Abstract
Tumor cells exhibit therapeutic stress resistance-associated secretory phenotype involving extracellular vesicles (EVs) such as oncosomes and heat shock proteins (HSPs). Such a secretory phenotype occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while [...] Read more.
Tumor cells exhibit therapeutic stress resistance-associated secretory phenotype involving extracellular vesicles (EVs) such as oncosomes and heat shock proteins (HSPs). Such a secretory phenotype occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as a soluble form known as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in the release of EV proteins including CD9 and epithelial-to-mesenchymal transition (EMT), a key event in tumor progression. EVs derived from CRPC cells promoted EMT in normal prostate epithelial cells. Some HSP family members and their potential receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein types found by mass spectrometry. The small EVs (30–200 nm in size) were released even in a non-heated condition from the prostate cancer cells, whereas the EMT-coupled release of EVs (200–500 nm) and damaged membrane vesicles with associated HSP90α was increased after heat shock stress (HSS). GAPDH and lactate dehydrogenase, a marker of membrane leakage/damage, were also found in conditioned media upon HSS. During this stress response, the intracellular chaperone CDC37 was transcriptionally induced by heat shock factor 1 (HSF1), which activated the CDC37 core promoter, containing an interspecies conserved heat shock element. In contrast, knockdown of CDC37 decreased EMT-coupled release of CD9-containing vesicles. Triple siRNA targeting CDC37, HSP90α, and HSP90β was required for efficient reduction of this chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, we define “stressome” as cellular stress-induced all secretion products, including EVs (200–500 nm), membrane-damaged vesicles and remnants, and extracellular HSP90 and GAPDH. Our data also indicated that CDC37 is crucial for the release of vesicular proteins and tumor progression in prostate cancer. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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13 pages, 1818 KiB  
Article
A 12-mer Peptide of Tag7 (PGLYRP1) Forms a Cytotoxic Complex with Hsp70 and Inhibits TNF-Alpha Induced Cell Death
by Elena A. Romanova, Tatiana N. Sharapova, Georgii B. Telegin, Alexei N. Minakov, Alexander S. Chernov, Olga K. Ivanova, Maxim L. Bychkov, Lidia P. Sashchenko and Denis V. Yashin
Cells 2020, 9(2), 488; https://doi.org/10.3390/cells9020488 - 20 Feb 2020
Cited by 8 | Viewed by 3407
Abstract
Investigation of interactions between a pro-inflammatory cytokine tumor necrosis factor (TNFα) and its receptor is required for the development of new treatments for autoimmune diseases associated with the adverse effects of TNFα. Earlier, we demonstrated that the innate immunity protein Tag7 (PGRP-S, PGLYRP1) [...] Read more.
Investigation of interactions between a pro-inflammatory cytokine tumor necrosis factor (TNFα) and its receptor is required for the development of new treatments for autoimmune diseases associated with the adverse effects of TNFα. Earlier, we demonstrated that the innate immunity protein Tag7 (PGRP-S, PGLYRP1) can interact with the TNFα receptor, TNFR1, and block the transduction of apoptotic signals through this receptor. A complex formed between the Tag7 protein and the major heat shock protein Hsp70 can activate TNFR1 receptor and induce tumor cell death via either apoptotic or necroptotic pathway. In this study, we show that a 12-mer peptide, designated 17.1, which was derived from the Tag7 protein, can be regarded as a novel TNFα inhibitor, also is able to form a cytotoxic complex with the heat shock protein Hsp70. This finding demonstrates a new role for Hsp70 protein in the immune response. Also, this new inhibitory 17.1 peptide demonstrates an anti-inflammatory activity in the complete Freund’s adjuvant (CFA)-induced autoimmune arthritis model in laboratory mice. It appears that the 17.1 peptide could potentially be used as an anti-inflammatory agent. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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16 pages, 1568 KiB  
Article
Radiosensitization of HSF-1 Knockdown Lung Cancer Cells by Low Concentrations of Hsp90 Inhibitor NVP-AUY922
by Annett Kühnel, Daniela Schilling, Stephanie E. Combs, Bernhard Haller, Melissa Schwab and Gabriele Multhoff
Cells 2019, 8(10), 1166; https://doi.org/10.3390/cells8101166 - 28 Sep 2019
Cited by 15 | Viewed by 4041
Abstract
The inhibition of heat shock protein 90 (Hsp90) a molecular chaperone for multiple oncogenic client proteins is considered as a promising approach to overcome radioresistance. Since most Hsp90 inhibitors activate HSF-1 that induces the transcription of cytoprotective and tumor-promoting stress proteins such as [...] Read more.
The inhibition of heat shock protein 90 (Hsp90) a molecular chaperone for multiple oncogenic client proteins is considered as a promising approach to overcome radioresistance. Since most Hsp90 inhibitors activate HSF-1 that induces the transcription of cytoprotective and tumor-promoting stress proteins such as Hsp70 and Hsp27, a combined approach consisting of HSF-1 knockdown (k.d.) and Hsp90 inhibition was investigated. A specific HSF-1 k.d. was achieved in H1339 lung cancer cells using RNAi-Ready pSIRENRetroQ vectors with puromycin resistance. The Hsp90 inhibitor NVP-AUY922 was evaluated at low concentrations—ranging from 1–10 nM—in control and HSF-1 k.d. cells. Protein expression (i.e., Hsp27/Hsp70, HSF-1, pHSF-1, Akt, ß-actin) and transcriptional activity was assessed by western blot analysis and luciferase assays and radiosensitivity was measured by proliferation, apoptosis (Annexin V, active caspase 3), clonogenic cell survival, alkaline comet, γH2AX, 53BP1, and Rad51 foci assays. The k.d. of HSF-1 resulted in a significant reduction of basal and NVP-AUY922-induced Hsp70/Hsp27 expression levels. A combined approach consisting of HSF-1 k.d. and low concentrations of the Hsp90 inhibitor NVP-AUY922 reduces the Hsp90 client protein Akt and potentiates radiosensitization, which involves an impaired homologous recombination mediated by Rad51. Our findings are key for clinical applications of Hsp90 inhibitors with respect to adverse hepatotoxic effects. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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Review

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24 pages, 2311 KiB  
Review
Molecular Chaperones in Osteosarcoma: Diagnosis and Therapeutic Issues
by Morgane Lallier, Louise Marchandet, Brice Moukengue, Celine Charrier, Marc Baud’huin, Franck Verrecchia, Benjamin Ory and François Lamoureux
Cells 2021, 10(4), 754; https://doi.org/10.3390/cells10040754 - 30 Mar 2021
Cited by 16 | Viewed by 3533
Abstract
Osteosarcoma (OS) is the most common form of primary bone tumor affecting mainly children and young adults. Despite therapeutic progress, the 5-year survival rate is 70%, but it drops drastically to 30% for poor responders to therapies or for patients with metastases. Identifying [...] Read more.
Osteosarcoma (OS) is the most common form of primary bone tumor affecting mainly children and young adults. Despite therapeutic progress, the 5-year survival rate is 70%, but it drops drastically to 30% for poor responders to therapies or for patients with metastases. Identifying new therapeutic targets is thus essential. Heat Shock Proteins (HSPs) are the main effectors of Heat Shock Response (HSR), the expression of which is induced by stressors. HSPs are a large family of proteins involved in the folding and maturation of other proteins in order to maintain proteostasis. HSP overexpression is observed in many cancers, including breast, prostate, colorectal, lung, and ovarian, as well as OS. In this article we reviewed the significant role played by HSPs in molecular mechanisms leading to OS development and progression. HSPs are directly involved in OS cell proliferation, apoptosis inhibition, migration, and drug resistance. We focused on HSP27, HSP60, HSP70 and HSP90 and summarized their potential clinical uses in OS as either biomarkers for diagnosis or therapeutic targets. Finally, based on different types of cancer, we consider the advantage of targeting heat shock factor 1 (HSF1), the major transcriptional regulator of HSPs in OS. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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19 pages, 1362 KiB  
Review
Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy
by Ji Woong Kim, Yea Bin Cho and Sukmook Lee
Cells 2021, 10(3), 670; https://doi.org/10.3390/cells10030670 - 17 Mar 2021
Cited by 21 | Viewed by 7010 | Correction
Abstract
Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER)-resident member of the heat shock protein 90 (HSP90) family. In physiological conditions, it plays a vital role in regulating biological functions, including chaperoning cellular proteins in the ER lumen, maintaining calcium homeostasis, and modulating [...] Read more.
Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER)-resident member of the heat shock protein 90 (HSP90) family. In physiological conditions, it plays a vital role in regulating biological functions, including chaperoning cellular proteins in the ER lumen, maintaining calcium homeostasis, and modulating immune system function. Recently, several reports have shown the functional role and clinical relevance of GRP94 overexpression in the progression and metastasis of several cancers. Therefore, the current review highlights GRP94’s physiological and pathophysiological roles in normal and cancer cells. Additionally, the unmet medical needs of small chemical inhibitors and the current development status of monoclonal antibodies specifically targeting GRP94 will be discussed to emphasize the importance of cell surface GRP94 as an emerging therapeutic target in monoclonal antibody therapy for cancer. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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23 pages, 2255 KiB  
Review
The Role of HSPB8, a Component of the Chaperone-Assisted Selective Autophagy Machinery, in Cancer
by Riccardo Cristofani, Margherita Piccolella, Valeria Crippa, Barbara Tedesco, Marina Montagnani Marelli, Angelo Poletti and Roberta M. Moretti
Cells 2021, 10(2), 335; https://doi.org/10.3390/cells10020335 - 05 Feb 2021
Cited by 31 | Viewed by 3945
Abstract
The cellular response to cancer-induced stress is one of the major aspects regulating cancer development and progression. The Heat Shock Protein B8 (HSPB8) is a small chaperone involved in chaperone-assisted selective autophagy (CASA). CASA promotes the selective degradation of proteins to counteract cell [...] Read more.
The cellular response to cancer-induced stress is one of the major aspects regulating cancer development and progression. The Heat Shock Protein B8 (HSPB8) is a small chaperone involved in chaperone-assisted selective autophagy (CASA). CASA promotes the selective degradation of proteins to counteract cell stress such as tumor-induced stress. HSPB8 is also involved in (i) the cell division machinery regulating chromosome segregation and cell cycle arrest in the G0/G1 phase and (ii) inflammation regulating dendritic cell maturation and cytokine production. HSPB8 expression and role are tumor-specific, showing a dual and opposite role. Interestingly, HSPB8 may be involved in the acquisition of chemoresistance to drugs. Despite the fact the mechanisms of HSPB8-mediated CASA activation in tumors need further studies, HSPB8 could represent an important factor in cancer induction and progression and it may be a potential target for anticancer treatment in specific types of cancer. In this review, we will discuss the molecular mechanism underlying HSPB8 roles in normal and cancer conditions. The basic mechanisms involved in anti- and pro-tumoral activities of HSPB8 are deeply discussed together with the pathways that modulate HSPB8 expression, in order to outline molecules with a beneficial effect for cancer cell growth, migration, and death. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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24 pages, 3046 KiB  
Review
The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer
by Graham Chakafana and Addmore Shonhai
Cells 2021, 10(2), 254; https://doi.org/10.3390/cells10020254 - 28 Jan 2021
Cited by 14 | Viewed by 3396
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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22 pages, 1821 KiB  
Review
Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients
by Michal Kielbik, Izabela Szulc-Kielbik and Magdalena Klink
Cells 2021, 10(1), 130; https://doi.org/10.3390/cells10010130 - 11 Jan 2021
Cited by 45 | Viewed by 5641
Abstract
Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various [...] Read more.
Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant disease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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21 pages, 1402 KiB  
Review
Molecular Chaperones and Proteolytic Machineries Regulate Protein Homeostasis in Aging Cells
by Boris Margulis, Anna Tsimokha, Svetlana Zubova and Irina Guzhova
Cells 2020, 9(5), 1308; https://doi.org/10.3390/cells9051308 - 24 May 2020
Cited by 28 | Viewed by 5118
Abstract
Throughout their life cycles, cells are subject to a variety of stresses that lead to a compromise between cell death and survival. Survival is partially provided by the cell proteostasis network, which consists of molecular chaperones, a ubiquitin-proteasome system of degradation and autophagy. [...] Read more.
Throughout their life cycles, cells are subject to a variety of stresses that lead to a compromise between cell death and survival. Survival is partially provided by the cell proteostasis network, which consists of molecular chaperones, a ubiquitin-proteasome system of degradation and autophagy. The cooperation of these systems impacts the correct function of protein synthesis/modification/transport machinery starting from the adaption of nascent polypeptides to cellular overcrowding until the utilization of damaged or needless proteins. Eventually, aging cells, in parallel to the accumulation of flawed proteins, gradually lose their proteostasis mechanisms, and this loss leads to the degeneration of large cellular masses and to number of age-associated pathologies and ultimately death. In this review, we describe the function of proteostasis mechanisms with an emphasis on the possible associations between them. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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24 pages, 1299 KiB  
Review
Membrane-Associated Heat Shock Proteins in Oncology: From Basic Research to New Theranostic Targets
by Maxim Shevtsov, Zsolt Balogi, William Khachatryan, Huile Gao, László Vígh and Gabriele Multhoff
Cells 2020, 9(5), 1263; https://doi.org/10.3390/cells9051263 - 20 May 2020
Cited by 45 | Viewed by 7250
Abstract
Heat shock proteins (HSPs) constitute a large family of conserved proteins acting as molecular chaperones that play a key role in intracellular protein homeostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular [...] Read more.
Heat shock proteins (HSPs) constitute a large family of conserved proteins acting as molecular chaperones that play a key role in intracellular protein homeostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSP families such as small HSPs, HSP40, HSP60, HSP70 and HSP90 have been found to be localized on the plasma membrane of malignantly transformed cells. In the current article, the role of membrane-associated molecular chaperones in normal and tumor cells is comprehensively reviewed with implications of these proteins as plausible targets for cancer therapy and diagnostics. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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20 pages, 1824 KiB  
Review
Molecular Mechanisms of Heat Shock Factors in Cancer
by Mikael Christer Puustinen and Lea Sistonen
Cells 2020, 9(5), 1202; https://doi.org/10.3390/cells9051202 - 12 May 2020
Cited by 31 | Viewed by 4672
Abstract
Malignant transformation is accompanied by alterations in the key cellular pathways that regulate development, metabolism, proliferation and motility as well as stress resilience. The members of the transcription factor family, called heat shock factors (HSFs), have been shown to play important roles in [...] Read more.
Malignant transformation is accompanied by alterations in the key cellular pathways that regulate development, metabolism, proliferation and motility as well as stress resilience. The members of the transcription factor family, called heat shock factors (HSFs), have been shown to play important roles in all of these biological processes, and in the past decade it has become evident that their activities are rewired during tumorigenesis. This review focuses on the expression patterns and functions of HSF1, HSF2, and HSF4 in specific cancer types, highlighting the mechanisms by which the regulatory functions of these transcription factors are modulated. Recently developed therapeutic approaches that target HSFs are also discussed. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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12 pages, 8545 KiB  
Review
RPAP3 C-Terminal Domain: A Conserved Domain for the Assembly of R2TP Co-Chaperone Complexes
by Carlos F. Rodríguez and Oscar Llorca
Cells 2020, 9(5), 1139; https://doi.org/10.3390/cells9051139 - 06 May 2020
Cited by 9 | Viewed by 3850
Abstract
The Rvb1-Rvb2-Tah1-Pih1 (R2TP) complex is a co-chaperone complex that works together with HSP90 in the activation and assembly of several macromolecular complexes, including RNA polymerase II (Pol II) and complexes of the phosphatidylinositol-3-kinase-like family of kinases (PIKKs), such as mTORC1 and ATR/ATRIP. R2TP [...] Read more.
The Rvb1-Rvb2-Tah1-Pih1 (R2TP) complex is a co-chaperone complex that works together with HSP90 in the activation and assembly of several macromolecular complexes, including RNA polymerase II (Pol II) and complexes of the phosphatidylinositol-3-kinase-like family of kinases (PIKKs), such as mTORC1 and ATR/ATRIP. R2TP is made of four subunits: RuvB-like protein 1 (RUVBL1) and RuvB-like 2 (RUVBL2) AAA-type ATPases, RNA polymerase II-associated protein 3 (RPAP3), and the Protein interacting with Hsp90 1 (PIH1) domain-containing protein 1 (PIH1D1). R2TP associates with other proteins as part of a complex co-chaperone machinery involved in the assembly and maturation of a growing list of macromolecular complexes. Recent progress in the structural characterization of R2TP has revealed an alpha-helical domain at the C-terminus of RPAP3 that is essential to bring the RUVBL1 and RUVBL2 ATPases to R2TP. The RPAP3 C-terminal domain interacts directly with RUVBL2 and it is also known as RUVBL2-binding domain (RBD). Several human proteins contain a region homologous to the RPAP3 C-terminal domain, and some are capable of assembling R2TP-like complexes, which could have specialized functions. Only the RUVBL1-RUVBL2 ATPase complex and a protein containing an RPAP3 C-terminal-like domain are found in all R2TP and R2TP-like complexes. Therefore, the RPAP3 C-terminal domain is one of few components essential for the formation of all R2TP and R2TP-like co-chaperone complexes. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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27 pages, 6307 KiB  
Review
HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity
by Thomas L. Prince, Benjamin J. Lang, Martin E. Guerrero-Gimenez, Juan Manuel Fernandez-Muñoz, Andrew Ackerman and Stuart K. Calderwood
Cells 2020, 9(4), 1046; https://doi.org/10.3390/cells9041046 - 22 Apr 2020
Cited by 36 | Viewed by 6749
Abstract
Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular [...] Read more.
Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular chaperones that promote cell viability by facilitating proteostasis. HSF1 activity is amplified in many tumor contexts in a manner that resembles a chronic state of stress, characterized by high levels of HSP gene expression as well as HSF1-mediated non-HSP gene regulation. HSF1 and its gene targets are essential for tumorigenesis across several experimental tumor models, and facilitate metastatic and resistant properties within cancer cells. Recent studies have suggested the significant potential of HSF1 as a therapeutic target and have motivated research efforts to understand the mechanisms of HSF1 regulation and develop methods for pharmacological intervention. We review what is currently known regarding the contribution of HSF1 activity to cancer pathology, its regulation and expression across human cancers, and strategies to target HSF1 for cancer therapy. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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54 pages, 2829 KiB  
Review
Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy
by Alexander Kabakov, Anna Yakimova and Olga Matchuk
Cells 2020, 9(4), 892; https://doi.org/10.3390/cells9040892 - 06 Apr 2020
Cited by 61 | Viewed by 10186
Abstract
Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be [...] Read more.
Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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26 pages, 2199 KiB  
Review
HSP70 Multi-Functionality in Cancer
by Zarema Albakova, Grigoriy A. Armeev, Leonid M. Kanevskiy, Elena I. Kovalenko and Alexander M. Sapozhnikov
Cells 2020, 9(3), 587; https://doi.org/10.3390/cells9030587 - 02 Mar 2020
Cited by 140 | Viewed by 12098
Abstract
The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most [...] Read more.
The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer “addiction” to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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16 pages, 6241 KiB  
Review
At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer
by Donat Kögel, Benedikt Linder, Andreas Brunschweiger, Silvia Chines and Christian Behl
Cells 2020, 9(3), 574; https://doi.org/10.3390/cells9030574 - 28 Feb 2020
Cited by 39 | Viewed by 4423
Abstract
BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins [...] Read more.
BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins by regulating their turnover via the two major protein degradation pathways, i.e. proteasomal degradation and macroautophagy. On the one hand, BAG3 competes with BAG1 for binding to HSP70, thereby preventing the proteasomal degradation of its client proteins. By functionally interacting with HSP70 and LC3, BAG3 also delivers polyubiquitinated proteins to the autophagy pathway. BAG3 exerts a number of key physiological functions, including an involvement in cellular stress responses, proteostasis, cell death regulation, development, and cytoskeletal dynamics. Conversely, aberrant BAG3 function/expression has pathophysiological relevance correlated to cardiomyopathies, neurodegeneration, and cancer. Evidence obtained in recent years underscores the fact that BAG3 drives several key hallmarks of cancer, including cell adhesion, metastasis, angiogenesis, enhanced autophagic activity, and apoptosis inhibition. This review provides a state-of-the-art overview on the role of BAG3 in stress and therapy resistance of cancer, with a particular focus on BAG3-dependent modulation of apoptotic signaling and autophagic/lysosomal activity. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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30 pages, 1092 KiB  
Review
Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy
by Chul Won Yun, Hyung Joo Kim, Ji Ho Lim and Sang Hun Lee
Cells 2020, 9(1), 60; https://doi.org/10.3390/cells9010060 - 24 Dec 2019
Cited by 165 | Viewed by 9065
Abstract
Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate [...] Read more.
Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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12 pages, 1426 KiB  
Review
Functional Compartmentalization of HSP60-Survivin Interaction between Mitochondria and Cytosol in Cancer Cells
by Ya-Hui Huang and Chau-Ting Yeh
Cells 2020, 9(1), 23; https://doi.org/10.3390/cells9010023 - 19 Dec 2019
Cited by 43 | Viewed by 5430
Abstract
Heat shock protein 60 (HSP60) and survivin reside in both the cytosolic and mitochondrial compartments under physiological conditions. They can form HSP60-survivin complexes through protein–protein interactions. Their expression levels in cancer tissues are positively correlated and higher expression of either protein is associated [...] Read more.
Heat shock protein 60 (HSP60) and survivin reside in both the cytosolic and mitochondrial compartments under physiological conditions. They can form HSP60-survivin complexes through protein–protein interactions. Their expression levels in cancer tissues are positively correlated and higher expression of either protein is associated with poor clinical prognosis. The subcellular location of HSP60-survivin complex in either the cytosol or mitochondria is cell type-dependent, while the biological significance of HSP60-survivin interaction remains elusive. Current knowledge indicates that the function of HSP60 partly rests on where HSP60-survivin interaction takes place. HSP60 has a pro-survival function when binding to survivin in the mitochondria through interacting with other factors such as CCAR2 and p53. In response to cell death signals, mitochondrial survivin functions through preventing procaspase activation. Degradation of cytosolic survivin leads to the loss of mitochondrial membrane potential and aberrant mitosis processes. On the other hand, HSP60 release from mitochondria to cytosol upon death stimuli might exert a pro-death function, either through stabilizing Bax, enhancing procaspase-3 activation, or increasing protein ubiquitination. Combining the knowledge of mitochondrial HSP60-survivin complex function, cytosolic survivin degradation effect, and pro-death function upon mitochondria release of HSP60, a hypothetical scenario for HSP60-survivin shuttling upon death stimuli is proposed. Full article
(This article belongs to the Special Issue Molecular Chaperones: Cancer and Cell Death)
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