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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). Reference 1.Blanco MA, Kang Y. Signaling pathways in breast cancer metastasis - novel insights from functional genomics. Breast Cancer Res 2011;13(2):206. 2.Lee HR, Jeung EB, Cho MH, Kim TH, Leung PC, Choi KC. 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