VET_8(1)_10_Amita Dubey.indd

Veterinary World, EISSN: 2231-0916
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REVIEW ARTICLE
Open Access
Heat shock proteins: a therapeutic target worth to consider
Amita Dubey1, K. S. Prajapati2, Madhu Swamy1 and V. Pachauri3
1. Department of Pathology, College of veterinary science & AH, NDVSU, Jabalpur, Madhya Pradesh, India;
2. Department of Pathology, College of veterinary science & AH, AAU, Anand, Gujarat, India; 3. Krishi Vigyan Kendra,
Jawaharlal Nehru Agricultural University, Sagar, Madhya Pradesh, India.
Corresponding author: Amita Dubey, e-mail: amiabhishek@rediffmail.com, KSP: kanti_prajapati@yahoo.com,
MS: vetpath@rediffmail.com, VP: dr.vivekinpachauri@gmail.com
Received: 08-09-2014, Revised: 20-11-2014, Accepted: 28-11-2014, Published online: 13-01-2015
doi: 10.14202/vetworld.2015.46-51. How to cite this article: Dubey A, Prajapati KS, Swamy M, Pachauri V (2015) Heat
shock proteins: a therapeutic target worth to consider, Veterinary World 8(1): 46-51.
Abstract
Heat shock proteins (HSPs) are the molecular chaperones, that are not only expressed during the normal growth process of cell
cycle consecutively, but also get induced in cells during various stress conditions produced by cellular insult, environmental
changes, temperature, infections, tumors etc. According to their molecular weight and functions, HSPs are divided into five
major families. HSP90, HSP70, HSP60 and HSP100 are the most studied members of the family. Experimental studies have
proved that overexpression and/or inhibition of HSPs play an important role in maintaining the tolerance and cell viability
under above-described stress conditions. HSP90 is found to be a promising candidate for the diagnosis, prognosis and
treatment of cancer. Similarly, HSP70, HSP60 and small HSPs experimentally and clinically have potential for the treatment
of neurodegenerative disease, ischemia, cell death, autoimmunity, graft rejection, etc. In a way, exploring, the cytoprotective
and immunoregulatory role of HSPs can open a new avenue for the drug discovery and treatment of critical diseases.
Keywords: heat shock protein, heat shock protein 70, heat shock protein 90, stress protein, small heat shock proteins.
Introduction
The heat shock response was first described
in 1962 by Ritossa and is named as heat shock proteins (HSPs) based on their increased synthesis after
heat shock in house fly [1]. Later it has been noted
that HSPs exist in all the organisms from bacteria
to humans, and they are among the most conserved
proteins known [2]. HSPs, are multimolecular complexes expressed constitutively (up 5-10% of the total
protein) under normal growth condition in cells and
act as molecular chaperones, which play a regulatory
role in the folding of proteins, intracellular transport of
proteins in cytosol, endoplasmic reticulum and mitochondria; repair or degradation of proteins and refolding of misfolded proteins [3]. In addition to being
constitutively expressed, these proteins are markedly induced (up to 15%) by a range of environmental, pathological, or physiological stimuli [4]. These
proteins are also modulated by nutrient deprivation,
oxidative stress, hypoxia-ischemia, apoptotic stimuli
and neuronal injury in the brain, etc. [5-7]. HSPs are
divided into five major families, HSP100, 90, 70, 60,
and the small HSP (sHSP)/О±-crystallins, according to
their molecular weight, structure and function. HSP
synthesis results in tolerance to insult, such as thermotolerance or stress tolerance in various organisms [8].
In various acute and chronic cell injuries, pathogenic
conditions such as malignancies, and infectious diseases overexpression of HSPs were found to be playing cytoprotective and immunoregulatory roles [9].
Copyright: The authors. This article is an open access article licensed
under the terms of the Creative Commons Attributin License (http://
creative commons.org/licenses/by/2.0) which permits unrestricted
use, distribution and reproduction in any medium, provided the
work is properly cited.
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Recently, HSP reactivity in autoimmune diseases and
transplantation have been proven to be down-regulated in the disease process [10,11]. Togetherness,
induction or inhibition of HSPs provides vast area
of therapeutic target for combating various diseases.
Considering, the regulatory role of HSPs in physiological and pathological conditions, HSPs have emerged
as potential drug candidates for drug development and
can be a breakthrough in the near future.
Regulation of HSPs
Stress condition causes protein unfolding, misfolding or aggregation, which triggers the stress
response that leads to the induction of gene transcription of proteins. HSP gene transcription is mediated
by the interaction of the heat shock factor (HSF1)
with heat shock elements (HSEs) in the HSP gene
promoter regions. In unstressed state, HSF1 is present in the cytoplasm as a latent monomeric molecule
(Figure-1). Under stress, HSF1 is hyperphosphorylated in a ras-dependent manner by members of the
mitogen-activated protein kinase (MAPK) subfamilies
(e.g. ERK1, JNK/SAPK, p38 protein kinase). HSF1
is then converted to phosphorylated trimers with the
capacity to bind DNA and translocates from the cytoplasm to the nucleus [12,13]. The generation of HSPs
is transient, and the presence of HSPs negatively
influences the protein homeostasis. The activity of
HSF trimers is downregulated by HSPs (e.g. HSP70)
and the heat shock binding protein 1 which is found in
the nucleus [9,14].
HSP90- A Potential Target for Cancer Therapy
HSP90 is one of the most studied and abundant
proteins of eukaryotic cells, comprising 1-2% of total
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Figure-1: Regulation and role of heat shock proteins.
proteins under non-stress conditions. It is evolutionarily conserved among species and is essential for cell
survival. HSP90 along with their co-chaperones, play
an important role in the folding of at least 200 specific
proteins of various signaling pathways, and in the
refolding of denatured proteins after stress [15,16].
HSP90 interacts with and stabilizes a growing list
of various kinases including several key members of
malignant transformation, such as the ErbB2, Src, Abl
or Met tyrosine kinases, or the Raf, Akt and cyclin-dependent serine kinases. Besides these, HSP90 is
necessary for the maturation of several transcription
factors, like the nuclear hormone receptors and the
hypoxia-inducible factor-1. HSP 90 client proteins
have been shown to be important for the development, proliferation and survival of several types of
cancer. Hence inhibiting the activities of HSP90 has
anti-cancer potential, N-terminal domain contains
a rather unique ATP-binding site, the Bergerat-fold
and more recently discovered C-terminal domain,
opened the new possibilities for the inhibition of this
chaperone to target the tumor [17,18]. In addition,
HSP90 binding has been shown to contribute to the
accumulation of tumor suppressor transcription factor
p53 [19,20]. 17-AAG (17-allylamino-17-demethoxygeldanamycin), Tanespimycin, Ganetespib are examples of chemical entity inhibiting the actions of HSP
90, emerging as a potential candidate for the treatment
of cancer like multiple myeloma, lung cancer, adenocarcinoma, pheochromocytoma, lymphoblastic leukemia [21-24].
HSP70 - A Potential Target for Neurodegenerative Diseases
Neurodegenerative diseases are great challenges
to the medical field. Effective therapies are rare and
applied after a vast amount of neurons is lost. Examples
of neurodegenerative diseases are Alzheimer�s disease, Parkinson’s disease, Spinal and bulbar muscular
atrophy, polyglutamine diseases, Huntington’s disease
(HD) and several forms of spinocerebellar ataxia, etc.
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A common pathogenesis of neurodegenerative disease is the misfolding, post-translation and aggregation of specific neuronal proteins [25]. A striking
finding noted in various in vitro and in vivo animal
experiments, are the expression of HSPs HSP70 and
HSP27 in surviving neuronal cells [26-28]. They were
found to be protecting the neurons against a variety of
adverse conditions including oxidative stress, alongwith anti-apoptotic activity by blocking the function
of several key pro-apoptotic factors. Overexpression
of HSP70 in Drosophila model of Parkinson disease and 5XFAD mouse model of Alzheimer disease delayed the progression of disease by autophagy of misfolded proteins and reduction of caspase-3
induced cell death [6,29,30]. Experiments have shown
protection of brain striatal lesion in HSP-70 overexpressing mice that developed the HD by Malonate
and 3-nitropropionic acid [7]. Similarly in lysosomal
diseases, severe brain damage occurs due to unstable
mutant enzyme proteins leading to rapid intracellular
degradation and loss of neuronal function. A chemical
inhibitor of HSP70 has been reported to stabilize the
enzyme activities [31,32].
HSP70 in Cerebral and Myocardial Ischemia
Increased expression of HSP70 is noted in
ischemic pneumbra indicating its important role in
attenuation of progression and protection of ischemia. Researchers have shown increased expression of inducible HSP70 in hypoxic neuron cultures
during thermal stress, global and focal cerebral ischemia [33,34]. Cerebral ischemia models using HSP70
overexpressing transgenic mice were protected
against myocardial ischemia and brain ischemia (middle cerebral artery occlusion) [35]. Constitutive overexpression of HSP70 in a cytomegalovirus enhancer
combined with a bactin promoter resulted in complete
recovery of infarct size [36]. Salvianolate, a chemical entity, unregulated the HSP22 and protected the
rat from cerebral ischemia-reperfusion injury [37].
Preconditioning with ischemia or chemical or thermal
stress had proved to enhance the expression of HSP
in the cell and increased the tolerance of the cell [38].
HSPs in Inflammation
Role of HSPs in induction of several pro-inflammatory cytokines and the signaling pathways are yet
to be fully clarified. Though the studies have shown
that overexpression of HSP60 induces the secretion
of interleukin 6 (IL-6) from human monocytes via
signaling through CD 14 and p38 MAPK, along with
the enhanced expression of TNF-О± and nitric oxide. It
also induces the expression of a range of cytokines,
including IL-12 and IL-15 [39-41]. Mammalian
HSP60 has been proved as a key target for T cell and
Ab responses in chronic inflammation and atherosclerosis [42]. Bacterial HSPs have shown to enhance the
expression of intracellular cell adhesion molecule and
vascular cell adhesion molecule. HSP70 acts through
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a CD14-dependent pathway to stimulate IL-1, IL-6
and TNF-О± production, indicating the fact that HSPs
are directly involved in the inflammation [41].
HSP in Transplantation
HSPs have been associated with allograft
rejection and in autoimmunity specially the HSP60.
Graft-infiltrating lymphocytes proliferate in response
to recombinant mycobacterial HSP65 and HSP71.
Multiple HSPs (HSp27, 60 and 70) are articulated in
renal allografts [10]. In rats and humans, increased
expression of HSP70 gene and protein are reported
in rejection of cardiac allografts. HSP expression was
also induced in the small intestinal epithelium of rat
after small-bowel transplantation and found to be
resistant to immunosuppressive drug tacrolimus [43].
These findings have pointed out that the HSP reactivity
in allograft would have a role in the acute and chronic
graft rejection [44]. However, the down-regulation of
HSPs in autoimmune and graft rejection process, activation of innate immunity by these proteins are also
meaningful as evident by the prolonged survival of
murine skin allograft at effect of HSP60 immunity. It
has also be reported that overexpression of HSP27 in
mouse hearts delays the allograft rejection by inhibiting the tissue damage. Indeed, the presence of HSPs
and HSP specific lymphocytes are not always indicative of a deleterious response, they might reflect an
anti-inflammatory protective response also [45,46].
HSP in Reproduction
HSP production is enhanced during germ cell
development and in-vitro embryo culture, and they
are among the first proteins produced during mammalian embryo growth. The spontaneous expression
of HSP as an essential part of embryo development
is well documented, and the presence or absence of
HSP influences various aspects of reproduction in
many species [47]. Increased HSP27, HSP60 and heat
shock cognate 70 in the endometrium are expressed
after ovulation and in the early secretory phase, which
is the critical period of endometrial receptivity for an
implanting embryo [4]. Studies on in vitro cultured
mouse and bovine embryos demonstrate that monoclonal antibodies to the 60 and 70 kDa HSPs (HSP60,
HSP70) inhibit early embryo development. Genital
tract infections, especially chronic Chlamydia trachomatis infections of the fallopian tubes, result in the
generation of immunity to conserved regions that are
present on both the chlamydial and human HSP60
molecules [48]. HSPs are consecutively expressed
and have their role in all stages of spermatogenesis
as evident in various studies on experimental animals and human. HSP70 knockout mice resulted in a
failed meiosis, massive apoptosis, and male infertility, in another experiment HSP 90 knockout mice displayed sterility because of morphological abnormality. Similarly, disruption of sHSP, HSPB10 resulted in
lower sperm motility and male infertility in a rat [49].
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SHSPs
Mammalian HSP27 (HSPB1) and О¬B-crystallin
(HSPB5) belong to the family of sHSPs. In human,
20 different sHSPs have been characterized but only
few of them, such as HSP27, HSP22 and О¬B-crystallin, are true HSPs. The structural organization of
sHSPs appears to be a crucial factor, which controls
the activity of these proteins [14]. sHSP is constitutively expressed in tissues with high rates of oxidative
metabolism, including, the heart, type I and type IIa
skeletal muscle fibers, brain, eye and oxidative
regions of the kidney. Their expression in these organs
indicates these can be therapeutic targets for neurodegenerative diseases, myopathies, asthma, cataracts
and cancers [50,51]. HSP27 is involved in cell immunity, inflammation, thermoregulation, tumorogenesis,
and apoptosis. HSP27 in murine L929 cell line blocks
the Fas/Apo-1 mediated cell death. It also protects the
actin and intermediate filaments from the fragmentation and modulates the ROS glutathione levels [52].
Similarly, HSP22 is probably involved in the cell
proliferation regulation, cardiac hypertrophy, apoptosis, neuromuscular health and carcinogenesis [53].
Another member of family О±B-crystallin has shown to
have a protective effect on myocardial cells and retina
from the oxidative injury [54-56].
HSPs in Veterinary Research
Romanucci demonstrated that HSP27, HSP72
and HSP90 are involved in canine mammary gland
carcinogenesis [54]. In addition, HSP27 appears to be
implicated in tumor invasiveness and that is indicative
of a poor prognosis. In veterinary literature, high levels
of HSP60 and HSP70 were reported in canine transmissible venereal tumor (CTVT), and it was thought
that these HSPs could be considered potential markers for CTVT cells [57-59]. More recent studies have
shown high levels HSP70 expression in canine mammary tumors confirming that HSP expression cannot
be relied upon for the recognition of a specific tumor
histological type. Bovine leukemia virus (BLV) infection up-regulates the expression of HSPs which in turn
could augment the humoral response. Anti-HSP70
activity was examined in the sera of 34 BLV-infected
cattle and 40 healthy controls by ELISA. Significantly
higher activities (p<0.001) were observed in BLVinfected animals [60]. Several studies have proposed
the implication of HSP in prion diseases. Serrano
et al., demonstrated that HSPs are involved in gliosis
and inflammatory reactions rather than in anti-apoptotic processes in natural scrapie [61].
Conclusion
HSPs are emerging as therapeutic targets for
human as well as veterinary medicine. Though a
lot has been studied in recent years, there are still
many aspects of HSP that remain puzzling. On one
hand, HSPs appears to be associated with several
pathological conditions, on the other side these are
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ubiquitously expressed and have a physiological role.
HSPs are implicated in all phases of cancer from proliferation, impaired apoptosis and sustained angiogenesis to invasion and metastasis. The presence
of abnormal HSP levels in several human tumors
suggests that these proteins could be used as diagnostic and/or prognostic markers, whilst the direct
correlation between HSP expression and drug resistance in neoplastic tissues means they can also be
used to predict cancer response to specific treatment.
Experimental and clinical studies with HSPs showed
a new opportunity for the treatment of ischemia and
neurodegenerative diseases. The observation that
HSPs directly or indirectly elicit potent immunoregulatory activities give a new perspective on the
roles of HSPs and anti-HSP reactivity in autoimmunity, transplantation, vascular disease, and other conditions. Though the HSPs have also been successfully targeted in clinical trials, still there is scope for
exploring its expression and inhibitory effects on the
normal and as well as stressed cells, best mimic animal model and translation of the experimental work
to the clinical condition. Similarly sHSPs are also
emerging as fascinating class of proteins, might be
crucial for future therapeutic strategies for critical
diseases such as cancer, neurodegenration, etc., if the
scientists are able to unravel developmental mechanisms, gene transcription and tissue- functions.
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Author’s Contributions
AD conceptualized and prepared initial version
of the manuscript. VP helped in the designing and
literature collection and reference arrangement. KSP
and MS reviewed the manuscript for critical scientific
correction and helped to structure the manuscript in
its final shape.
16.
17.
Acknowledgments
The authors are thankful to the Dr. Abhishek
Dubey for his support.
Competing Interests
18.
19.
The authors declare that they have no competing
interest.
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