Δευτέρα 20 Απριλίου 2020

Role of Molecular Chaperones in Carcinogenesis: Mechanism, Diagnosis, and Treatment

Role of Molecular Chaperones in Carcinogenesis: Mechanism, Diagnosis, and Treatment:

jo.banner.jpgThe role of molecular chaperones in carcinogenesis is a central theme of many current research efforts worldwide. It is pertinent to clarify that while various chaperones are Hsps, many are not, and vice versa not all Hsps are chaperones. An example of the latter is Hsp32, better known as heme oxygenase-1 (HO-1), which is dealt with in one of the articles in this Special Issue because of its probable involvement in certain types of carcinogenesis. Likewise, long noncoding RNAs are currently emerging as modulators of metastasization, and one contribution deals with this interesting new issue in Oncology.


While the involvement of chaperones in cancer progression has been extensively reported, the mechanism of their participation in carcinogenesis is largely unknown. Nevertheless, extant information is enough for considering these molecules as a promising biomarker for diagnosis and patient monitoring in some types of cancer and also promising to be used as therapeutic targets or agents. The aim of this Special Issue is to gather information about these themes.

Characterization of mechanisms underlying the role of molecular chaperones in cancer is an emerging issue in the oncology field. Molecular chaperones are involved in many biochemical pathways essential for tumor cell survival, and this makes them candidates for consideration as key players in the biochemistry of cancer. Therefore, the development of tools for diagnosis and treatment targeting chaperones is currently an active discipline within oncology.

Some malignant tumors can be classified as “chaperonopathies by mistake” because the molecular chaperones in the cancer cells contribute to their proliferation and mediate their resistance against antitumor defenses and facilitate metastasization. Chaperones are thus helping the “enemy” so to speak and are therefore “mistaken.” These chaperones work for the tumor rather than to defend the host. Efforts must be directed toward finding ways to eliminate or block these “mistaken” chaperones. This strategy of negative chaperonotherapy is currently being incorporated to the battery of other approaches such as chemo- and immunotherapy to treat cancer.

In this Special Issue, various examples of tumors in which Hsp-chaperones and a Hsp that is not a chaperone play a noteworthy role are discussed along with the potential of chaperonotherapy.

The review by Das et al. highlights recent advances and perspectives in Hsp-based cancer immunotherapy. The importance of research on the role of Hsp-chaperones, specifically Hsp27, Hsp60, Hsp70, and Hsp90, in modulating carcinogenesis is discussed, emphasizing their critical role in determining the balance between protective and destructive immunological responses within the tumor microenvironment; the possibilities involving Hsp27, Hsp70, and Hsp90 are clearly schematized in the first figure of the article, while pathways of presentation of tumor antigens by Hsps to antigen-presenting cells (APCs) are summarized in the second figure. Along this line of thought, Hsps are seen as an effective therapeutic option for some malignant tumors, including melanoma. Recent progress in this field is discussed, including anticancer vaccines, specifically those based on Hsp70 and Hsp90 are summarized in Table 1 of the article. These vaccines have been shown to be active against a spectrum of tumor antigens since they induce T-lymphocyte activation as well as stimulation of antigens uptake by APCs.

In the review by Fucarino et al., emphasis is given to the study of the molecular mechanisms in carcinogenesis that involve chaperones. Specifically, they focus on the chaperonin Hsp60 alone or in complex with Hsp10, and its implication in lung cancer, and also analyze the broad set of Hsp60 interactors, some of which are listed in Table 1 of the article. Noteworthy is the relationship of the fragile histidine triad (FHIT) protein, a tumor-suppressor factor, with Hsp60 and Hsp10 in complex, in mitochondria. FHIT, like many other mitochondrial proteins, depends for its correct folding on the Hsp60/Hsp10 chaperoning complex; it is, therefore, possible that a chaperonopathy affecting either one or the other of these two chaperonins will result in a decrease of tumor suppression, namely, will favor tumor growth. This is certainly a topic for future investigation because it may help find ways to apply positive chaperonotherapy to oppose tumor progression by administering Hsp60 and/or Hsp10 or boosting their activities, thereby reenforcing the chaperoning of FHIT protein correct folding, which will thus become an effective tumor suppressor. Continuous stress conditions in the respiratory mucosa, such as cigarette smoking, increase Hsp60 chaperonin levels outside mitochondria. High levels of this chaperonin are associated with tumor deterioration in some cancer types, but in other types, the reverse is seen, namely, tumor progression is favored probably due to inhibition of apoptosis and senescence in tumor cells by the chaperonin.

The paper by Wu et al. examines the effects of long noncoding RNA lnc-TLN2-4:1 in gastric cancer (GC). Forty-nine patients were recruited for this study who had not been submitted to chemotherapy before and were followed for four years. The authors demonstrate that lnc-TLN2-4:1 is decreased in GC tissue compared with matched normal tissue and is involved in poor overall survival rates of GC patients. Moreover, they show that lnc-TLN2-4:1 overexpression inhibits GC cell migration and invasion, but does not affect GC cell proliferation, suggesting its involvement as a tumor suppressor of GC metastases. In conclusion, Inc-TLN2-4:1 is a suppressor of metastasization and when it is under-regulated like in GC the survival rate of patients is poor.

The paper by Castruccio Castracani et al. presents data on the effect of estradiol E2 in human glioblastoma-multiforme (GBM) cells, focusing on proliferative capacity and mitochondrial functions. Expression of genes involved in mitochondrial biogenesis, oxidative phosphorylation, and dynamics was measured. Also, nuclear translocation of Nrf2 was assessed. The results showed that E2 increases the proliferation of glioblastoma cells and changes the expression of various genes among those investigated, e.g., those involved in oxidative phosphorylation. E2 also increased nuclear translocation of Nrf2 resulting in the induction of one of its target genes, hemeoxygenase-1, which is associated with the increase of both, chemoresistance and tumor-cell proliferation. These data show that E2 induces GBM proliferation and enhances its mitochondrial physiology, both of which certainly play a role in the well-known resistance of this tumor to all kinds of therapies, and open new avenues for developing novel treatment strategies.

In the paper by Kam et al., the authors report on the compound 2-methoxyestradiol as a potential anticancer agent, using as a model the A375 melanoma cells. They also studied the effect of polyphenol ferulic acid using the same cells. By applying MTT, flow cytometry, and Western blotting, the authors examined the molecular mechanisms underpinning the compounds’ actions. These are partly related to the reduction of Hsp60 and Hsp90 levels and the induction of nitric oxide in A375 melanoma cells. The authors did not observe any changes in Hsp70 levels after 2-methoxyestradiol and ferulic acid treatment separately or in combination. This information is pertinent to evaluate chemoresistance mechanisms since Hsp70 accumulation reduces induction of cancer-cell death and decreases the antitumor efficacy of some therapeutic agents.

Conflicts of Interest
The editors declare that they have no conflicts of interest regarding the publication of this Special Issue.

Acknowledgments
The authors would like to thank the authors for their contributions to this Special Issue. ECdeM was partially supported by IMET (IMET contribution number: IMET 20-006).

Everly Conway de Macario
Alessandro Pitruzzella
Agata Grazia D’Amico

Copyright
Copyright © 2020 Everly Conway de Macario et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Chaperone (protein)

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A top-view of the GroES/GroEL bacterial chaperone complex model
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding and the assembly or disassembly of other macromolecular structures. Chaperones are present when the macromolecules perform their normal biological functions and have correctly completed the processes of folding and/or assembly. The chaperones are concerned primarily with protein folding. The first protein to be called a chaperone assists the assembly of nucleosomes from folded histones and DNA and such assembly chaperones, especially in the nucleus,[1][2] are concerned with the assembly of folded subunits into oligomeric structures.[3]
One major function of chaperones is to prevent both newly synthesised polypeptide chains and assembled subunits from aggregating into nonfunctional structures. It is for this reason that many chaperones, but by no means all, are heat shock proteins because the tendency to aggregate increases as proteins are denatured by stress. In this case, chaperones do not convey any additional steric information required for proteins to fold. However, some highly specific 'steric chaperones' do convey unique structural (steric) information onto proteins, which cannot be folded spontaneously. Such proteins violate Anfinsen's dogma,[4] requiring protein dynamics to fold correctly.
Various approaches have been applied to study the structure, dynamics and functioning of chaperones. Bulk biochemical measurements have informed us on the protein folding efficiency, and prevention of aggregation when chaperones are present during protein folding. Recent advances in single-molecule analysis[5] have brought insights into structural heterogeneity of chaperones, folding intermediates and affinity of chaperones for unstructured and structured protein chains.

Location and functions[edit]

Some chaperone systems work as foldases: they support the folding of proteins in an ATP-dependent manner (for example, the GroEL/GroES or the DnaK/DnaJ/GrpE system). Although most newly synthesized proteins can fold in absence of chaperones, a minority strictly requires them for the same. Other chaperones work as holdases: they bind folding intermediates to prevent their aggregation, for example DnaJ or Hsp33.[6] Chaperones can also work as disaggregases, i.e. they can interact with aberrant protein assemblies and revent them to monomers.[7] Some chaperones can assist in protein degradation, leading proteins to protease systems, such as the ubiquitin-proteasome system in eukaryotes.[8]
Many chaperones are heat shock proteins, that is, proteins expressed in response to elevated temperatures or other cellular stresses.[9] The reason for this behaviour is that protein folding is severely affected by heat and, therefore, some chaperones act to prevent or correct damage caused by misfolding.
Macromolecular crowding may be important in chaperone function. The crowded environment of the cytosol can accelerate the folding process, since a compact folded protein will occupy less volume than an unfolded protein chain.[10] However, crowding can reduce the yield of correctly folded protein by increasing protein aggregation.[11][12] Crowding may also increase the effectiveness of the chaperone proteins such as GroEL,[13] which could counteract this reduction in folding efficiency.[14]
More information on the various types and mechanisms of a subset of chaperones that encapsulate their folding substrates (e.g. GroES) can be found in the article for chaperonins. Chaperonins are characterized by a stacked double-ring structure and are found in prokaryotes, in the cytosol of eukaryotes, and in mitochondria.
Other types of chaperones are involved in transport across membranes, for example membranes of the mitochondria and endoplasmic reticulum (ER) in eukaryotes. A bacterial translocation—specific chaperone maintains newly synthesized precursor polypeptide chains in a translocation-competent (generally unfolded) state and guides them to the translocon.[15]
New functions for chaperones continue to be discovered, such as bacterial adhesin activity, induction of aggregation towards non-amyloid aggregates,[16] suppression of toxic protein oligomers via their clustering,[17][18] and in responding to diseases linked to protein aggregation[19] (e.g. see prion) and cancer maintenance.[20]

Human chaperone proteins[edit]

Chaperones are found in, for example, the endoplasmic reticulum (ER), since protein synthesis often occurs in this area.

Endoplasmic reticulum[edit]

In the endoplasmic reticulum (ER) there are general, lectin- and non-classical molecular chaperones helping to fold proteins.

Nomenclature and examples of bacterial and archaeal chaperones[edit]

There are many different families of chaperones; each family acts to aid protein folding in a different way. In bacteria like E. coli, many of these proteins are highly expressed under conditions of high stress, for example, when the bacterium is placed in high temperatures. For this reason, the term "heat shock protein" has historically been used to name these chaperones. The prefix "Hsp" designates that the protein is a heat shock protein.

Hsp60[edit]

Hsp60 (GroEL/GroES complex in E. coli) is the best characterized large (~ 1 MDa) chaperone complex. GroEL is a double-ring 14mer with a hydrophobic patch at its opening; it is so large it can accommodate native folding of 54-kDa GFP in its lumen. GroES is a single-ring heptamer that binds to GroEL in the presence of ATP or ADP. GroEL/GroES may not be able to undo previous aggregation, but it does compete in the pathway of misfolding and aggregation.[24] Also acts in mitochondrial matrix as molecular chaperone.

Hsp70[edit]

Hsp70 (DnaK in E. coli) is perhaps the best characterized small (~ 70 kDa) chaperone.
hsp70 pocket for substrate binding
The Hsp70 proteins are aided by Hsp40 proteins (DnaJ in E. coli), which increase the ATP consumption rate and activity of the Hsp70s.
It has been noted that increased expression of Hsp70 proteins in the cell results in a decreased tendency toward apoptosis.
Although a precise mechanistic understanding has yet to be determined, it is known that Hsp70s have a high-affinity bound state to unfolded proteins when bound to ADP, and a low-affinity state when bound to ATP.
It is thought that many Hsp70s crowd around an unfolded substrate, stabilizing it and preventing aggregation until the unfolded molecule folds properly, at which time the Hsp70s lose affinity for the molecule and diffuse away.[25] Hsp70 also acts as a mitochondrial and chloroplastic molecular chaperone in eukaryotes.

Hsp90[edit]

Hsp90 (HtpG in E. coli) may be the least understood chaperone. Its molecular weight is about 90 kDa, and it is necessary for viability in eukaryotes (possibly for prokaryotes as well).
Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell.
Each Hsp90 has an ATP-binding domain, a middle domain, and a dimerization domain. Originally thought to clamp onto their substrate protein (also known as a client protein) upon binding ATP, the recently published structures by Vaughan et al. and Ali et al. indicate that client proteins may bind externally to both the N-terminal and middle domains of Hsp90.[26][27]
Hsp90 may also require co-chaperones-like immunophilins, Sti1, p50 (Cdc37), and Aha1, and also cooperates with the Hsp70 chaperone system.[28][29]

Hsp100[edit]

Hsp100 (Clp family in E. coli) proteins have been studied in vivo and in vitro for their ability to target and unfold tagged and misfolded proteins.
Proteins in the Hsp100/Clp family form large hexameric structures with unfoldase activity in the presence of ATP. These proteins are thought to function as chaperones by processively threading client proteins through a small 20 Å (2 nm) pore, thereby giving each client protein a second chance to fold.
Some of these Hsp100 chaperones, like ClpA and ClpX, associate with the double-ringed tetradecameric serine protease ClpP; instead of catalyzing the refolding of client proteins, these complexes are responsible for the targeted destruction of tagged and misfolded proteins.
Hsp104, the Hsp100 of Saccharomyces cerevisiae, is essential for the propagation of many yeast prions. Deletion of the HSP104 gene results in cells that are unable to propagate certain prions.

History[edit]

The investigation of chaperones has a long history.[30] The term "molecular chaperone" appeared first in the literature in 1978, and was invented by Ron Laskey to describe the ability of a nuclear protein called nucleoplasmin to prevent the aggregation of folded histone proteins with DNA during the assembly of nucleosomes.[31] The term was later extended by R. John Ellis in 1987 to describe proteins that mediated the post-translational assembly of protein complexes.[32] In 1988, it was realised that similar proteins mediated this process in both prokaryotes and eukaryotes.[33] The details of this process were determined in 1989, when the ATP-dependent protein folding was demonstrated in vitro.[34]

Clinical significance[edit]

There are many disorders associated with mutations in genes encoding chaperones (i.e. multisystem proteinopathy) that can affect muscle, bone and/or the central nervous system.[35]

See also[edit]

References[edit]

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