Download Potential role(s) of cysteine cathepsins in cancer progression and

Potential role(s) of cysteine cathepsins in cancer progression
and metastasis
Abstract
Cancer is the result of damage to the genetic system, i.e., dysfunction of the DNA repair system, resulting in dysregulated
expression of various molecules, leading to cancer formation, migration, and invasion. In cancer progression, several
proteases play a critical role in metastasis; however, their biological mechanism in cancer metastasis is not clearly
understood. Among these proteases, cathepsins are a family of lysosomal proteases found in most animal cells. Cathepsins
have an important role in protein turnover of mammalian, and are classified into 15 types based on their structure as serine
(cathepsin A and G), aspartic (cathepsin D and E), and cysteine cathepsins (cathepsin B, C, F, H, K, L, O, S, V, X, and W).
Cysteine cathepsins appear to accelerate the progression of human and rodent cancers, which can be a biomarker of the
potency of malignancy or metastasis in mammalian. Overexpression of cyteine cathepsins causes the activation of
angiogenesis promoting factor, whereas their downregulation reduces the angiogenesis of cancer progression. Under
physiological conditions, cysteine cathepsins are essential in inflammation, infection, and cancer development. Activity of
cysteine proteases, i.e., cathepsin B, is required for cancer progression or metastasis. Elevation of cysteine cathepsin is
associated with cancer metastasis, angiogenesis, and immunity. Therefore, in this review, we suggest that cysteine cathepsin
may be an anticancer target of strong clinical interest, although the exact mechanism of cathepsins in cancer metastasis is
under investigation.
Introduction
Cancer is a disease defined as a mass of cells in uncontrolled growth and division, which has been a major cause of d
eath in humans [1, 2]. This malignant symptom is a result of damaged genetic system, i.e., dysfunctions of DNA repair
system, resulting in abnormal dysfunction, resulting in cancer formation, migration and invasion [3]. In cancer progres
sion, several proteases play a critical role in metastasis which is not clearly understood in biological mechanism [4]. In
recent studies, an accelerated activity of proteases has been shown to associate with poor prognosis of patients in a w
ide range of cancers including breast [5, 6]. Proteases determines the pathological and physiological consequences in
organ as a molecular modulator of phosphorylation signaling pathways such as extracellular-signal-regulated kinase (
ERK) involved in the regulation of meiosis or mitosis in cells [7]. The expression of diverse proteases has been linked t
o cancer cell migration, invasion, immunity and angiogenesis in many cancers [8]. In this review, we highlight that abu
ndant expression of cysteine proteases along with interaction with other proteases is associated with stimulation of ca
ncer formation and progression or metastasis of human cancers.
Diverse proteases in cancer progression
Various proteases induce the degradation of extracellular matrix (ECM) components to initiate a spread step of cance
r cells from primary site toward distant new site [9]. Most of proteolytic enzymes consist of a catalytic residue; metallo,
aspartic, cysteine, serine, and threonine. These proteolytic activities modulate the signaling in important biological sys
tem such as cell proliferation, apoptosis, immune system, and bone regeneration [10-12].
Among these proteases responsible for proteolytic action, cathepsins are a family of lysosomal proteases found in m
ost of animals [13]. Cathepsin members are usually carried as a form of zymogens to form lysosomes and activated at
condition of low pH, which is required for maturation of autocatalytic mechanism. Cathepsins are classified by their ac
tive site and target of cleavage. athepsins have a critical role in protein turnover of mammalian, and are composed of
15 types based on their structure as serine (cathepsin A and G), aspartic (cathepsin D and E), cysteine cathepsins (cath
epsin B, C, F, H, K, L, O, S, V, X and W) [14]. Recent studies indicated that activation of cathepsins can be an effective ta
rget of cancer therapy in clinic to reduce the potential to metastasis [15-17]. Cysteine cathepsins affect the cancer pro
gression as along with interaction with metalloproteinase (MMPs) or serine protease urokinase plasminogen activator
(uPA) [18, 19]. MMPs and uPA also stimulated the tumorigenesis depending on specific tissue to disruption of commu
nication of extracellular component with membrane to degrade the ECM for cancer progression [20]. However, it is wi
dely accepted that cysteine protease is strongly involved in cancer destination more than MMPs or others. There are n
ot sufficient understanding of mechanism about how cysteine cathepsins promote initiation of cancer growth and me
tastasis [21]. During not only cancer proliferation but also angiogenesis, cysteine cathepsins activities tend to be assoc
iated with angiogenesis.
Cysteine cathepsins family
The regulation of protein turnover by proteases is required for progress of cancer, especially, invasion and metastasis
[22]. An increased expression of cathepsins is frequently detected in human cancers, suggesting strong correlation of
a member of cathepsins with tumorigenic processes [23]. Cathepsin family is responsible for a variety of cellular photo
lytic mechanism involved in maturation of protein in immune system, hormone generation and signaling transition on
mammalian [24]. There are existing 11 cystein cathepsins in human, which play a general role as intracellular acidic pr
oteases in endolysomal compartments [25] (Table1).
Table 1. Specific cystei
ne cathepsins and their relation with diseases
Cysteine cathepsins are synthesized with a signal peptide that is cleavage target of N-terminus and undergoes glycos
ylation in lumen of endoplasmic reticulum (ER) [26]. Cysteine cathepsins are synthesized as an inactive proenzyme for
m, which is referred as zymogens. After elimination of signal peptides at N-terminus, cysteine cathepsin becomes a siz
e of 20~30 kDa via maturation in lysosome. Cysteine cathepsin family is composed of two domains in a V-shaped clef
t, which edge has an active site where the target substrate peptide binds. This sequence allows specificity for cathepsi
ns with specific tissues [27]. For example, although cysteine cathepsins have similar structure with others, cathepsin L
has affinity to aromatic residues more than other cysteine cathepsin. This specificity of cysteine cathepsin contributes
the remarked expression of that in specific cell type to perform protein turnover in time, which is evidenced by deficie
nt mice in recent studies [28, 29]. These growing interests about cysteine cathepsin reveal the closed relation of these
enzymes with several diseases including cancers [30].
Overexpression of cysteine cathepsin in cancers
An involvement of cysteine cathepsin in cancer progress is widely discussed and accepted in recent. Upregulation of
cysteine cathepsin has been demonstrated in various cancers, including breast, ovarian, pancreatic, lung and liver [31].
In addition, enhanced expression of cathepsin B has been observed in premalignant lesions situated, among others, w
ithin colon, thyroid, brain, liver, breast and prostate. Highly enhanced cysteine cathepsins are involved in activation of
other proteases, i.e., MMPs, plasmin, and cathepsin D [32]. These disruptions of cysteine cathepsins contribute the dis
sociation of cells from basement membrane for extravasations to metastasis. Cysteine cathepsins can directly degrade
ECM components such as fibronectin, collagen, laminin, resulting in imbalance of cell-cell communication [33]. Strong
evidence that cysteine cathepsins have relation with cancer progression shows in which the expression of protease inh
ibitors is found to reduce for process of a premalignant form to malignant cancers (Fig. 1).
Fig. 1. Potential role(s)
of cysteine cathepsins in cancer development. Cysteine cathepsins can directly degrade ECM components such as fibr
onectin, collagen, laminin, which results in imbalance of cell-cell communication. Cysteine cathepsins affect the cancer
progression as along with interaction with metalloproteinase (MMPs) or serine protease urokinase plasminogen activa
tor (uPA).
Lysosomal cysteine cathepsin S has been implicated in a number of cancers, which fact suggests that cathepsin S is cl
osely related with cancer progression on several specific organs of humans. Detected overexpression of cysteine cathe
psin S in the hepatocytes cells in patients is analogized as one of the key events in normal cells to be cancerous cells.
Therefore, inhibition of cysteine cathepsin members has been focused on targeto mechanism of cancer therapy in rec
ent [34]. In xenograft models, inhibitors of the cysteine cathepsin family have shown to lead to suppress tumor prolife
ration in mouse model bearing the pancreatic islet cancer cell. The recent study continues to evaluate whether this us
e of a cathepsin inhibitor will increase an antitumor efficacy in the patients with chemotherapy [35].
Physiological role of cathepsin B in cancers
Cathepsin B is a papain family, which abundantly exist in mammalian cells as along with degradation of cysteine pepti
de. Its activation is regulated in many physiological processes, such as wound healing, call proliferation and apoptosis
[36]. In addition, cathepsin B among cysteine cathepsins has been accelerated in the progression of human and roden
t cancers, which can be a biomarker the potency of malignancy or metastasis in mammals [17]. Development of cance
rs is caused by disorders in gene expression and protein function of cell cycle, protein turnover and cell division. This
phenomenon can be also explained by upregulation of cathepsin cysteine proteases in cancers compared to normal s
urrounding cells [37].
Among 11 members of cysteine cathepsins, cathepsin B may serve as major factors of oral cancers to initiate the spre
ad toward distant site. Single nucleotide polymorphisms (SNPs) of cathepsin B is affected by environmental chemicals
causing cancer risk [38], suggesting that the functional structure of cathepsin B contribute to the poor diagnosis of ca
ncer patients exposed to carcinogens. Environmental disrupting chemicals (EDCs) can have influence both transcriptio
nal and translational regulation of cathepsin B in breast cancer, indicating that proteases affected by EDCs may be a bi
omolecular cause of increased occurrence of cancers in industrialized society [39, 40]. This relation cathepsin B with p
oor outcome of cancer patients has been revealed in recent numerous studies based on oncogenic processes in huma
ns [41]. However, specific targeting of cathepsin B without other proteases is not useful to reduce cancer growth dram
atically, and this is probably because cysteine cathepsins including B may be cross-linked with others in complicated si
gnaling pathways [42]. Therefore, it is required to examine multifunction of cysteine cathepsins in cancer progression
and to reveal process of amplification and activation of proteases in human cancer.
Cathepsin cysteine proteases in angiogenesis
During not only cancer proliferation but also angiogenesis, cathepsin B activities tend to be increased and associated
with the angiogenesis [43]. Angiogenesis play a role in supplement of oxygen and nutrients for cancer development b
y blood vessels, which is a critical event into cancer acquiring uncontrolled proliferative character. In angiogenesis, en
dothelial cells of microvascular tissues secrete and activate proteolytic protein for penetration of the vascular membra
ne and the interstitial extracellular matrix [44]. In this progression, cathepsin family is also activated by degradation of
signal peptides. Recent studies reported that the expression of cathepsin B and L has been implicated in gliomas and
neuronal diseases [45]. Overexpression of cathepsin B caused the reduction of VEGF-mediated signaling pathway, whe
reas down-regulation of cathepsin B stimulated the response of VEGF [46].
Cathepsin S is well known to contribute to permit penetration in angiogenesis. Recent study reveals that stimulatory f
actors, i.e., inflammatory cytokines or angiogenic factors, induced the expression of cathepsin S. However, an inhibitor
of cathepsin S reduced the formation of microtubule connection. Cathepsin S null mice reduced the invasion of collag
en components such as collagens type I and IV [47]. However, these mice showed the defective formation of microves
sels during wound healing. In addition, cysteine cathepsins regulate the biosynthesis of anti-angiogenic peptides, ind
ucing the activation of angiogenic peptides from laminin, and revealing a molecular regulating role in angiogenesis [4
8]. This insufficient angiogenesis by defective cathepsin S cannot be reversed by presence of normal vascular growth f
actors, including EGF or FGF which play a critical role in microvessel developments [49]. These results demonstrate mu
ltifunction of cathepsin S in angiogenic mechanism of human. Taken together, the reduction cysteine cathepsins can
be a key to block angiogenesis in cancer development [50].
Cysteine cathepsin in immune system
In physiological system, cysteine cathepsins are essential in inflammation, infection and cancer in general pathologica
l processes in human body [51]. Cysteine cathepsin is involved in signaling modulation of proteins related with infecti
on, antigen presentation, and acceleration of immune cells in overall immune system [52]. The expression of cysteine
cathepsins are highly observed in antigen-presenting cells [53]. Along with other lysosomal proteases, cysteine and as
partyl cathepsins play a role in digesting antigenic proteins. Among them, cysteine cathepsins are involved in the maj
or histocompatibility complex class (MHC) II and process of antigen presentation [54]. Cysteine cathepsins are a major
promoting factor in the degradation of the complex of the invariant chain (Ii) into the class II-associated Ii peptide (CL
IP). This fact demonstrated cysteine cathepsin-induced signaling as a potential target in the treatment for immune dis
eases.
A number of drugs to reduce cysteine cathepsin activity are valuable to immune disease [55]. For example, cathepsin
X is one of lysosomal cysteine dependent proteases. Activity and amount of cathepsin X regulates signaling transport
er of the immune cells in inflammation. Cysteine cathepsins stimulate macrophage antigen-1 (Mac-1) receptor-depen
dent adhesion, resulting in the decrease with lymphocyte proliferation during the phagocytosis [29, 56]. In addition, th
ey have been shown to suppress proliferation of immune cells such as human mononuclear cells in blood [57]. Howev
er, almost of cysteine cathepsins are expressed and activated in antigen-presenting cells (APC). It was of interest that c
ysteine cathepsins are involved in the turnover of antigenic T cell epitopes in human APC. Therefore, abnormal functio
n of cysteine cathepsins affects directly immune system in human [58].
Conclusion
Various cancers are known to overexpress proteases, which contribute to cancer growth, metastasis, angiogenesis and
immunity in human. Among the elevated proteases, cysteine cathepsins appear to correlate with increased potential o
f invasion of cancer cells. Cysteine cathepsins stimulate the progression of human and rodent cancers, which can be a
biomarker of the potency of malignancy or metastasis in mammals. Overexpression of cysteine cathepsin causes the a
ctivation of angiogenesis promoting factor, while its downregulation reduces the angiogenesis of cancer progression.
Taken together, cysteine cathepsin may be an anticancer target of strong clinical interest, although the exact mechani
sm of cathepsins in cancer metastasis is under investigation.
Acknowledgements
This work was supported by the Priority Research Centers Program through the National Research Foundation of Kor
ea (NRF) funded by the Ministry of Education, Science and Technology (MEST) of the Korean government (2011-0031
403).
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