Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Cathepsin B

  • Dora Cavallo-Medved
  • Bonnie F. Sloane
  • Kamiar Moin
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101523


 CatB;  CathB;  CB1;  CPSB;  CTSB;  EC

Historical Background

Cathepsin derives from the Greek word “kathepsein” (i.e., to digest) and was coined in 1929 to describe digestive peptidases that are active in a slightly acidic environment (Willstätter and Bamann 1929). Cathepsin B, originally named cathepsin B1, was the first and remains the best-characterized member of the C1 family of papain-like, lysosomal cysteine peptidases. First purified from human liver in 1973 (Barrett 1973), cathepsin B is ubiquitously expressed in most cell and tissue types. The first complete protein sequence for cathepsin B, isolated from rat liver, was reported in 1983 (Takio et al. 1983). The first cDNA sequences for cathepsin B were published in 1985 (San Segundo et al. 1985). Cathepsin B exhibits both endopeptidase and exopeptidase activities, which are modulated by its occluding loop (Illy et al. 1997) and blocked by endogenous inhibitors of cysteine cathepsins (Barrett 1986). The main role for cathepsin B is for nonspecific, bulk turnover of intracellular and extracellular proteins in the acidic late endosomal/lysosomal compartments. Over the past three decades, however, many studies have established a correlation between the upregulation and alterations in the subcellular localization of cathepsin B and various pathologies including cancer and arthritis.

Protein Function

Cathepsin B is a member of the family of cysteine cathepsins and is synthesized as a preproenzyme of 339 amino acids with a calculated molecular weight of approximately 38 kDa (reviewed in Kirschke et al. 1995; Mort and Buttle 1997). Cathepsin B is a bilobal protein with its catalytic site located at the interface between the two lobes (Musil et al. 1991). The amino acids cysteine, histidine and aspartic acid comprise the catalytic triad of the enzyme with cysteine on the left lobe interacting with histidine on the right lobe to catalyze peptide bond cleavage. Cathepsin B exhibits both endopeptidase and exopeptidase activity. As an endopeptidase, cathepsin B favors amino acids with a large hydrophobic side chain in the P2 site of the protein/peptide substrate (i.e., two residues N-terminus of the scissile bond), although it will also accept arginine at this site (Hasnain et al. 1993). As an exopeptidase, cathepsin B can remove two amino acids (dipeptide) from the C-terminus of a polypeptide substrate, thus classifying the enzyme as a peptidyldipeptidase. Unlike other cysteine cathepsins, cathepsin B also contains an occluding loop, which consists of 18 amino acids between Pro107 and Asp124. Two salt bridges between the occluding loop and the mature enzyme (at positions His110-Asp22 and Arg116-Asp224) partially block the substrate-binding cleft thereby promoting its peptidyldipeptidase activity (Illy et al. 1997; Musil et al. 1991). Displacement of the occluding loop is pH dependent and modulates cathepsin B activity by favoring exopeptidase and endopeptidase activities at acidic and neutral/alkaline pHs, respectively. Endopeptidase activity at neutral/alkaline pHs is due to disruption of the salt bridges between the occluding loop and the mature enzyme, thus allowing for increased flexibility and displacement of the occluding loop (Nagler et al. 1997). In procathepsin B, the occluding loop cannot interact with the active-site cleft of the enzyme due to the propeptide that passes directly across the active-site cleft (Turk et al. 1996).

Under normal physiological conditions, active cathepsin B is localized to the late endosomal/lysosomal compartment and is primarily involved in routine turnover of both intracellular and extracellular proteins, thus maintaining homeostatic metabolic activity within cells. Other cellular functions for cathepsin B include the regulation of prohormone and proenzyme activation, antigen processing, inflammatory responses against antigens, tissue remodeling, and apoptosis (reviewed in Mort and Buttle 1997). For example, in the thyroid, proteolytic processing of the prohormone thyroglobulin (Tg) by secreted cathepsin B (i.e., nonlysosomal) generates the thyroid hormones thyroxine (T4) and triiodothyronine (T3) (Brix et al. 1996; Linke et al. 2002).

Expression and activity of cathepsin B have been correlated with a number of pathologies including cancer, arthritis, pancreatitis, cardiovascular disease, and Alzheimer’s disease. In cancer, overexpression of cathepsin B has been reported in breast, prostate, brain, esophageal, gastric, lung, ovarian, thyroid, skin, and colon cancers (reviewed in Aggarwal and Sloane 2014; Gondi and Rao 2013; Jedeszko and Sloane 2004; Mohamed and Sloane 2006; Roshy et al. 2003). Upregulation of cathepsin B expression is predictive of poor prognosis in several tumors such as colon (Campo et al. 1994; Ruan et al. 2016) and ovarian (Scorilas et al. 2002) carcinomas. Moreover, a positive correlation between cathepsin B expression and metastasis of carcinoma cells to lymph nodes has been shown in breast (Foekens et al. 1998), prostate (Sinha et al. 2002), pancreas (Gopinathan et al. 2012), and gastric (Czyzewska et al. 2008) cancers. Overexpression of cathepsin B is often accompanied by an altered trafficking of the enzyme to the plasma membrane and secretion into the extracellular milieu (reviewed in Cavallo-Medved and Sloane 2003; Mohamed and Sloane 2006; Roshy et al. 2003). Pericellular and extracellular localization of active cathepsin B allows the enzyme to directly degrade and remodel the extracellular matrix (ECM) and thereby promote migration and invasion of tumor cells. In addition, cathepsin B participates in proteolytic networks as an activator of both downstream serine and metallo-proteases that also contribute to tumorigenesis and invasion. In the tumor microenvironment, cathepsin B has been shown to play a critical role in crosstalk between tumor and stromal (e.g., fibroblasts, monocytes, macrophages, endothelial) cells that leads to increased tumor growth, angiogenesis, and invasion (reviewed in Aggarwal and Sloane 2014). Tumor-stromal crosstalk involving cathepsin B has also been shown to be mediated by proinflammatory signals such as interleukin-6 (Mohamed and Sloane 2006; Osuala et al. 2015). Possible mechanisms for the overexpression of cathepsin B in cancer cells are discussed below in the section “Regulation of Concentration.”

Historically in clinical practice, targeting cathepsin B using inhibitors as antitumor drugs has been challenging due to poor bioavailability, high toxicity, and off-target side effects (Turk 2006). More recently, however, nitroxoline (5-nitro-8-hydroxyquinoline), a potent, selective, and reversible inhibitor of cathepsin B, was shown to significantly reduce degradation of ECM and tumor cell invasion in 2D and 3D in vitro models and abrogate tumor growth, angiogenesis, and metastasis formation in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models (Mirkovic et al. 2015). These results suggest a need for further preclinical and clinical studies to validate the potential for nitroxoline and its derivatives as potential antitumor drugs. Cathepsin B-activated cytotoxic prodrugs and antibody-drug conjugates that target overexpression of the enzyme in tumors (i.e., intracellularly and pericellularly) and their microenvironment have also been the focus for new antitumor therapies. Results from both preclinical and clinical trials of several cathepsin B-activated drugs have shown some promise (for review see Weidle et al. 2014). In particular, a cathepsin B-cleavable doxorubicin prodrug was shown to reduce metastasis in human hepatocarcinoma with less side effects than doxorubicin itself (Wang et al. 2013).

Upregulation of cathepsin B has been shown in the synovium of rheumatoid arthritis patients and, in particular, in activated fibroblast-like synoviocytes at the site of joint destruction (Hansen et al. 2000; Tong et al. 2014). Inhibition of cathepsin B in fibroblast-like synoviocytes reduces migration and invasion of these cells via mechanisms that reduce expression of MMP-2 and F-actin and activation of focal adhesion kinase (Tong et al. 2014). In the synovial fluid, cathepsin B participates in collagen degradation, which is inhibited by CA074, a highly selective inhibitor of cathepsin B, consistent with a role for cathepsin B in the progression of the disease (Hashimoto et al. 2001). In osteoarthritis, cathepsin B and its RNA variant CB(-2) (i.e., a cathepsin variant lacking exon 2) are overexpressed in osteoarthritic cartilage and osteophytes as compared to normal cartilage, an effect correlated with an increase in secretion of procathepsin B and its proteolytic activation (Berardi et al. 2001). Furthermore, active cathepsin B has been shown to correlate with the severity of the disease as determined through use of an activity-based probe for this enzyme (Ben-Aderet et al. 2015).

Cathepsin B plays a role in acute pancreatitis by prematurely activating latent precursor digestive enzymes such as trypsinogen within zymogen granules of pancreatic acinar cells. Activation of trypsinogen to trypsin results in the release of organelle-bound cathepsin B into the cytosol, triggering death of pancreatic acinar cells through both the intrinsic pathway of apoptosis or necrosis (reviewed in Lerch and Halangk 2006; Talukdar et al. 2016; Van Acker 2006). In vitro assays have demonstrated that cathepsin B can activate one of the resident zymogens, trypsinogen, into its active form, trypsin. Moreover, in vivo studies using cathepsin B-deficient mice revealed that 90% of the intrapancreatic trypsinogen activation during pancreatitis is dependent upon cathepsin B activity (Halangk et al. 2000; Sendler et al. 2016; Van Acker 2006; Van Acker et al. 2002).

In atherosclerosis, cathepsin B plays roles in lipid metabolism (reviewed in Lutgens et al. 2007). Uptake of modified (i.e., oxidized) LDL particles results in localization of cathepsin B within the cytoplasm, most likely via the disruption of lysosomal membranes, and results in the activation of caspases and subsequent apoptosis (Li et al. 2001; Li and Yuan 2004). In atherosclerotic lesions of apoE-deficient mice, cathepsin B mRNA and protein levels are increased in areas adjacent to the lumen and within macrophages (Chen et al. 2002). In vivo imaging of cathepsin B localized the enzyme in atherosclerotic plaques (Chen et al. 2002), thus suggesting that detecting the enzyme might be useful as a diagnostic tool for atherosclerosis. Recent studies using activity-based probes to assess active cathepsin B in carotid plaques suggest that active cathepsin B may be diagnostic for high-risk plaques (Abd-Elrahman et al. 2016). Indeed, antiatherosclerotic therapies using atorvastatin and glucosamine reduce the cathepsin B-related imaging signal in apoE-deficient mice (Kim et al. 2009). In contrast, a protective role for cathepsin B in atherosclerosis has also been suggested. In smooth muscle cells, inhibition of cathepsin B activity reduces lysosomal degradation of modified LDL and this accumulation of LDL induces foam cell formation (Tertov and Orekhov 1997).

Cathepsin B has also been localized to secretory vesicles of neuronal cells, and its activity within these vesicles produces β-amyloid (Aβ) peptides by cleavage of amyloid precursor protein (APP) at the wild-type (wt) β–secretase site (Hook et al. 2005, 2008). In transgenic mice expressing human APP containing the wt β-secretase site, which is present in most Alzheimer’s disease patients, inhibition of cathepsin B activity results in a reduction of Aβ peptide accumulation and amyloid plaque load and an improvement in memory deficit (Hook et al. 2008). In cathepsin B knockout mice, there is a decrease in Aβ production and C-terminal β-secretase fragmentation, supporting cathepsin B as a potential therapeutic target for inhibitors to reduce brain Aβ generated from wt APP associated with Alzheimer’s disease (Hook et al. 2009). More recent studies revealed that cathepsin B is involved in the production of pyroglutamate amyloid-β peptides (pGlu-Aβ), a more harmful form of Aβ peptides found in Alzheimer’s disease. Use of cathepsin B inhibitor E64d and its derivatives to reduce formation of pGlu-Aβ in mouse models of Alzheimer’s disease shows promise for targeting cathepsin B as a potential therapeutic strategy against the disease (Hook et al. 2014).

Regulation of Activity

Cathepsin B is an important participant within cellular proteolytic networks. One of the activating proteases for cathepsin B is cathepsin D, an aspartic protease (van der Stappen et al. 1996). Cathepsin B is also activated by a number of other proteases, including the serine proteases cathepsin G, urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), and elastase (Dalet-Fumeron et al. 1996; Dalet-Fumeron et al. 1993). Additionally, the interaction between cathepsin B and uPA is reciprocal, as cathepsin B can also activate pro-uPA (Kobayashi et al. 1991). Cathepsin B can also undergo autocatalytic activation within the acidic environment of late endosomes and lysosomes. This is a bimolecular process that results in proteolytic removal of the propeptide and subsequent activation of the enzyme (Rozman et al. 1999). Autoactivation of cathepsin B can be accelerated by binding of the enzyme to polyanionic polysaccharides such as dextran sulfate and naturally occurring glycosaminoglycans, including heparin, heparin sulfate, and chondroitin sulfate (Caglic et al. 2007).

Activity of cathepsin B is also modulated by the position of its occluding loop. The occluding loop has two histidine residues that at acidic pH interact with the substrate-binding cleft and exhibit carboxypeptidase activity (i.e., exopeptidase) of the enzyme. At acidic pH, cathepsin B has been shown to degrade types II, IX, and XI collagen (Maciewicz et al. 1990). Displacement of the occluding loop away from the active-site cleft, as observed under neutral/alkaline conditions, allows protein substrates access to the active site and the enzyme to function as an endopeptidase (Illy et al. 1997; Musil et al. 1991). Interaction of the occluding loop of cathepsin B with heparin sulfate at the cell surface structurally stabilizes the enzyme under alkaline conditions and potentiates endopeptidase activity (Almeida et al. 2001). This interaction is significant in possibly associating cathepsin B to the plasma membrane and regulating its enzymatic activity.

Cathepsin B activity is regulated directly by endogenous inhibitors such as cystatins (Barrett 1986; Turk et al. 1997; Turk and Bode 1991). Cystatins are inhibitors of papain-like cysteine proteases and are subdivided into three families (i.e., cystatin I, II, and III) based on their distinct molecular structures, distribution in the body, and physiological roles (reviewed in Abrahamson et al. 2003). The actions of these inhibitors require that the occluding loop of cathepsin B be displaced, allowing the inhibitor to bind to the active-site cleft. Cystatin C, an extracellular inhibitor belonging to the cystatin II family, binds to cathepsin B in two steps: (1) an initial weak binding of the inhibitor to the enzyme, followed by (2) a conformational change in the enzyme that is required to displace the occluding loop and allow for a tighter inhibitor-enzyme bond (Musil et al. 1991; Nycander et al. 1998). Inhibition of cathepsin B by cystatin A/stefin A, a cytosolic cystatin I family inhibitor, has also been reported to occur via a similar two step mechanism (Pavlova et al. 2000; Renko et al. 2010). Moreover, a structural analysis of cystatin A/stefin A binding to cathepsin B suggests that the relocation of the occluding loop is an energy-efficient event (Renko et al. 2010). Other members of the cystatin superfamily that inhibit cathepsin B activity include cystatin B/stefin B, also a member of the cystatin I family (Turk et al. 1997), equistatin from sea anemone (Lenarcic et al. 1997), clitocypin from fungi (Brzin et al. 2000), saxiphilin from bullfrog (Lenarcic et al. 2000), and chum salmon egg cysteine proteinase inhibitor (Yamashita and Konagaya 1996). In contrast, kininogens, members of the cystatin III superfamily, do not show any inhibitory activity against cathepsin B due to their inability to displace the occluding loop (Naudin et al. 2010). Interestingly, a noncystatin inhibitor, Spi2A, a member of the antichymotrypsin family of serine protease inhibitors (serpins), has also been shown to inhibit cathepsin B activity and protect cells from caspase-dependent apoptosis (Liu et al. 2003). Unlike other inhibitors of the antichymotrypsin family, Spi2A is not secreted and resides in the cytoplasm.

Interactions with Ligands and Other Proteins

As a constitutively expressed lysosomal protease involved in normal protein turnover, cathepsin B interacts with and hydrolyzes a number of protein substrates. Redistribution of cathepsin B to the cell surface and extracellular milieu allows the enzyme access to ECM protein substrates such as laminin, fibronectin, collagen, and E-cadherin (Buck et al. 1992; Gocheva et al. 2006; Maciewicz et al. 1990). In addition, localization to and activity of cathepsin B at the plasma membrane occurs via cell surface–binding proteins.

Using a yeast-two hybrid system, several proteins including S100A10 (i.e., the light chain of the annexin II heterotetramer (AIIt)) (Mai et al. 2000b), DP1, and MAGE-3 (Mai and Sloane, unpublished data) have been identified as cathepsin B binding partners. Further in vitro and in vivo analyses (i.e., GST-pull down and coimmunoprecipitation assays) revealed that S100A10 binds procathepsin B but not the mature form of the enzyme (Mai et al. 2000a). More specifically, these proteins were shown to colocalize on the surface of both tumor cells (Mai et al. 2000a) and endothelial cells (Cavallo-Medved et al. 2009) and within their caveolin-enriched membrane microdomains (Cavallo-Medved et al. 2005, 2009; Cavallo-Medved and Sloane 2003). AIIt at the cell surface has also been shown to bind heparin (Kassam et al. 1997), which along with heparin sulfate binds cathepsin B at the cell surface (Almeida et al. 2001). The binding of cathepsin B to either heparin or heparin sulfate occurs at the His111 residue of the occluding loop and results in the stabilization of the enzyme at alkaline pH (Almeida et al. 2001). AIIt also binds the serine proteases plasminogen (Kassam et al. 1998) and tPA (Hajjar et al. 1994), an activator of cathepsin B. As previously noted, cathepsin B activates pro-uPA (Kobayashi et al. 1991), which in turn is hypothesized to initiate proteolytic events involving the activation of plasminogen, tPA, and matrix metalloproteinases (MMPs) at the cell surface (reviewed in Cavallo-Medved and Sloane 2003). Other binding partners for cell surface cathepsin B are α2-macroglobulin and its receptor, which also binds both pro-PA and its inhibitor PAI-1 (Arkona and Wiederanders 1996).

Yeast-two hybrid experiments have also identified the human homologue of SETA binding protein 1 (hSB1) (Liu et al. 2006b), bikunin, and TSRC1 (Liu et al. 2006a) as potential cathepsin B binding proteins. HSB1 binds the multifunctional adaptor protein SETA; bikunin is a member of the Kunitz-type protease inhibitor family and inhibits trypsin, plasmin, and leukocyte elastase, whereas the function of TSRC1 remains unknown. Interactions between these proteins and cathepsin B were confirmed using in vitro GST pull-down assays and in vivo coimmunoprecipitation experiments (Liu et al. 2006a, b). Bikunin, hSB1, and TSRC1 also colocalize with cathepsin B in cellular lysosomes; however, their roles in regulating cathepsin B activity remain unknown. Overexpression of hSB1 and bikunin has been shown to suppress tumor necrosis factor (TNF)-triggered apoptosis in OV-90 ovarian cancer cells, although only bikunin expression reduced cathepsin B activity in these cells (Liu et al. 2006a, b).

Regulation of Concentration

Cathepsin B expression can be regulated at multiple levels. The cathepsin B gene locus is on chromosome 8 (8p22) (Fong et al. 1992), the site of an amplicon that contributes to the malignant progression of esophageal carcinoma. Overexpression of cathepsin B associated with this amplicon is hypothesized to contribute to tumor progression (Hughes et al. 1998). Amplification of the cathepsin B gene has also been found in transformed rat ovarian cells (Abdollahi et al. 1999).

The cathepsin B gene consists of 12 exons (Gong et al. 1993). In human gastric adenocarcinoma cells, there are an additional two small exons, 2a and 2b (Berquin et al. 1995). There have been at least three promoter regions identified as sites for the initiation of transcription (reviewed in Yan and Sloane 2003). The major promoter is located just upstream of exon 1 with other promoter regions upstream of exons 3 and 4. This promoter is TATA-less and GC-rich with a single transcription start site, initially classifying cathepsin B as a housekeeping gene (Berquin et al. 1995). This promoter also contains six Sp1, four Ets, and one USF (E-box) binding sites all located 200 bp upstream of the transcription start site (Yan et al. 2000). Transcriptional activation of the cathepsin B promoter by several transcription factors such as USF1, USF2, Sp1, Sp3, and Ets1 has been shown to play an important role in the regulation of cathepsin B expression (Chamberlain et al. 2010; Yan et al. 2000). Sp1 binding to GC-rich regions of the cathepsin B promoter upregulates cathepsin B expression (Yan et al. 2000). In murine melanoma cells, this results in increased cell invasion (Szpaderska et al. 2004). Binding of USF1 and USF2 to the E-box is required for cathepsin B promoter activity in both normal and tumor cells (Jane et al. 2002; Yan and Sloane 2003). On the other hand, a splice variant of USF2, USF2c, binds to the E-box element within the cathepsin B promoter and represses cathepsin B expression (Yan and Sloane 2004). Regulation of cathepsin B expression by Est1 is intriguing as this transcription factor is also upregulated in tumors and is associated with inflammatory and endothelial cells (Yan et al. 2000). Furthermore, Est1 induces expression of other proteases linked to malignant progression (Majerus et al. 1992).

Posttranscriptional regulation of cathepsin B gene expression has also been shown. For example, treatment of cells with phorbol ester increases cathepsin B expression by increasing the stability of the mRNA transcript (Berquin et al. 1999). Alternative splicing of the pre-mRNA of cathepsin B is another regulatory mechanism that mediates expression of the enzyme (Berquin and Sloane 1995; Gong et al. 1993; Tam et al. 1994). Two major mRNA species produced from the cathepsin B gene are 2.3 kb and 4.0 kb transcripts, the latter with an extended 3′untranslated region (UTR). Alternative splicing in the 5′-UTR results in six splice variants and splicing in the 5′-translated regions results in 2 cathepsin B transcripts, one lacking exon 2 [CB(-2)] and another lacking both exons 2 and 3 [CB(-2,3)] (Gong et al. 1993; Tam et al. 1994). Since the start codon is located in exon 3, the translated product of CB(-2,3) lacks both the signal peptide and the propeptide and therefore is not transported to intracellular vesicular compartments (Gong et al. 1993). Instead, the variant remains cytosolic (Mehtani et al. 1998). Functions of these cathepsin B splice variants are discussed below in the section “Splice Variants.”

Regulation of cathepsin B at the posttranslational level has also been reported. Transfection of colon epithelial cells with the K-ras4BG12V oncogene increases cathepsin B expression levels without altering mRNA levels (Yan et al. 1997). Similar results are observed in breast epithelial cells transfected with the c-Ha-ras oncogene (Rozhin et al. 1994). Other posttranslational mechanisms for regulation of cathepsin B expression include suppression by ligand activated proxisomal proliferator-activated receptor (PPAR) delta (Reichenbach et al. 2012). In human endothelial cells, the PPARα agonist Wy14643 also posttranslationally regulates cathepsin B by reducing the half-life of the protein. In addition, Wy14643 suppresses cathepsin B mRNA accumulation, a 5′alternative splice variant and protein expression by reduced binding of the transcription factors USF1/2 to an E-box within the cathepsin B promoter (Reichenbach et al. 2013).

Subcellular Localization

Cotranslational translocation of cathepsin B into the rough endoplasmic reticulum (rER) results in the formation of a preproenzyme containing 339 amino acids with the subsequent removal of the signal peptide (17 amino acids) (Fig. 1). Procathepsin B (43/46 kDa) is N-glycosylated at two potential sites (one in the propeptide region and another in the heavy chain of the enzyme). Procathepsin B is shuttled to the Golgi apparatus where further modification of the oligosaccharides to unique high-mannose carbohydrates occurs (Takahashi et al. 1984). Phosphorylation of the mannose residues directs the enzyme to the endosomal/lysosomal compartment via the mannose-6-phosphate receptor pathway. In the endosomal compartment, the enzyme is dissociated from the receptor and the 62 amino acid propeptide is removed from the N-terminus, along with 6 amino acids from the C-terminus, generating the mature single chain form of cathepsin B (31 kDa). Further processing may occur in the lysosomes where two amino acids between residues 47 and 50 are removed generating a mature double-chain form consisting of a heavy chain (25/26 kDa) and a light chain (5 kDa) that are linked via a disulfide bridge (reviewed in Mort and Buttle 1997).
Cathepsin B, Fig. 1

Cathepsin B network map. 1. Preprocathepsin B at the rough endoplasmic reticulum. 2. Procathepsin B (43 kDa) in the rough endoplasmic reticulum (removal of amino acids 1–18). 3. Procathepsin B (43/46 kDa) in the rough endoplasmic reticulum (2 glycosylation sites: one in propeptide and another in mature region). 4. Mature single chain cathepsin B (31 kDa) in the late endosome/lysosome (removal of amino acids 1–62 (pro-region)). 5. Mature double chain cathepsin B (25/26 kDa plus 5 kDa) in lysosome (removal of two amino acids between residues 47 and 50; removal of C-terminal six amino acids; disulfide bond formation between six chains). 6. Cathepsin B associated with plasma membrane. 7. Cathepsin B secreted into extracellular milieu

Redistribution of cathepsin B to the cell surface has been observed in both normal cells such as cytotoxic T lymphocytes (Balaji et al. 2002) and endothelial cells (Cavallo-Medved et al. 2009) as well as in a number of different types of cancer cells (reviewed in Cavallo-Medved and Sloane 2003; Roshy et al. 2003). Cathepsin B has also been localized to focal adhesions in tumor cells (Rempel et al. 1994; Sameni et al. 1995) and podosomes in transformed fibroblasts (Tu et al. 2008). Moreover, the metastatic potential of three melanoma cell lines is positively correlated with an increase in cathepsin B activity in plasma membrane fractions (Sloane et al. 1986). Subcellular fractionation of metastatic murine melanoma cells revealed the presence of the 31 kDa single chain form of cathepsin B on the plasma membrane as three isozymes with pI values of 5.33, 5.2, and 5.1 (Moin et al. 1998; Sloane et al. 1986). Activity of cell surface cathepsin B has been demonstrated with both real-time enzymatic assays and live-cell proteolysis assays using confocal imaging (Linebaugh et al. 1999; Sameni et al. 2000). Trafficking of cathepsin B to the cell surface can be mediated by several factors including the expression of oncogenic Ha-ras (Sloane et al. 1994) and Ki-ras (Cavallo-Medved et al. 2003). Specific localization of cathepsin B to caveolae on the cell surface was identified in colorectal and breast carcinoma cells as well as in endothelial cells (Cavallo-Medved et al. 2005, 2009; Cavallo-Medved and Sloane 2003). In these cells, cathepsin B is associated with AIIt within caveolar membrane microdomains along with other proteases including uPA and MMP-2 (Cavallo-Medved et al. 2005, 2009). Moreover, a decrease in expression of caveolin-1, the main structural protein of caveolae, leads to a decrease in cathepsin B distribution to caveolae and a decrease in pericellular ECM degradation and invasion (Cavallo-Medved et al. 2005).

Cathepsin B secretion by normal and cancer cells has been shown to occur via both constitutive and inducible pathways (Gao et al. 2015; Kuliawat and Arvan 1994; Linebaugh et al. 1999; Moon et al. 2016). Secretion of cathepsin B has been suggested to be due to exocytosis of lysosomes, supported by the evidence that treatment of cells with pH 6.5 alters the distribution of vesicles containing cathepsin B to the cell surface resulting in increased secretion of the enzyme (Gao et al. 2015; Rozhin et al. 1994). Membrane vesicles shed from B16 melanoma cells, perhaps vesicles now designated as exosomes, contain cathepsin B (Cavanaugh et al. 1983). Other factors including interleukin-6 (Mohamed et al. 2010), phorbol ester (Guo et al. 2002), 12-(S)-hydroxyeicosatetraenic acid (12-S-HETE) (Honn et al. 1994), and interferon-γ (Lemaire et al. 1997) increase cathepsin B secretion by mechanisms that have not been elucidated.

Cathepsin B has also been localized to the cytoplasm where it may act as a proapoptotic mediator (Guicciardi et al. 2000). In hepatocytes exposed to TNF, caspase-8 activation is associated with the release of cathepsin B from acidic vesicles into the cytoplasm, which results in the subsequent release of cytochrome c from mitochondria and activation of caspases 9 and 3 (Guicciardi et al. 2000). Moreover, hepatocytes isolated from cathepsin B knockout mice are resistant to TNF-induced apoptosis (Guicciardi et al. 2000). Further studies also identified cathepsin B as a major contributor to an apoptotic cascade upstream of mitochondria in TNF-mediated hepatocyte apoptosis and the progression of the TNF-induced liver damage (Guicciardi et al. 2001). Contrarily, others have found that genetic ablation of cathepsin B increases tumor-associated apoptosis, thus indicating that cathepsin B is not always a proapoptotic mediator (Bojic et al. 2007; Gocheva et al. 2006).

Nuclear distribution of cathepsin B has been observed for an artificially truncated form of the enzyme (Bestvater et al. 2005). Localization of truncated cathepsin B to the nucleus is mediated by a signal within the heavy-chain domain of the enzyme and results in cell death. Immunofluorescence and biochemical data also demonstrated nuclear localization of a proteolytically active variant of cathepsin B that is slightly smaller than the proform in thyroid carcinoma cells, in which their interactions with DNA-associated proteins may contribute to thyroid malignancy (Tedelind et al. 2010).

Major Sites of Expression

Analysis of the promoter region of cathepsin B indicates that the enzyme is encoded by a housekeeping gene and thus is constitutively expressed in all tissues. Nonetheless, upregulation of cathepsin B mRNA and protein has been observed in cancer cells including prostate, colon, breast, esophageal, gastric, pancreatic, lung, ovarian, thyroid, and gliomas and melanomas (reviewed in Aggarwal and Sloane 2014; Cavallo-Medved et al. 2003; Jedeszko and Sloane 2004; Roshy et al. 2003). In particular, cathepsin B has been shown to localize to the leading invasive edges of tumors. Cathepsin B staining revealed that the enzyme is distributed to the basal pole of cancer cells. In colon cancer, this redistribution is observed in late adenomas (Yan et al. 1997), a stage subsequent to the activation of Ki-ras. Cathepsin B and the uPA receptor, uPAR, are both highly expressed in glioma stem cells, and upregulation of uPAR and cathepsin B promotes malignant self-renewal of these cells through increased expression of hedgehog signaling components and high expression of Sox2 and Bmi1 (Gopinath et al. 2013).

Expression of cathepsin B in stromal cells (i.e., fibroblasts, endothelial cells, macrophages) within the tumor microenvironment has also been reported. In colon cancer, cathepsin B overexpression is observed in both inflammatory macrophages and tumor-associated fibroblasts (Campo et al. 1994). Macrophages associated with breast and prostate tumors also express high levels of cathepsin B (Castiglioni et al. 1994; Fernandez et al. 2001). Tumors from transgenic mice expressing human cathepsin B that were crossed with transgenic polyoma virus middle T oncogene breast cancer mice (mouse mammary tumor virus-PymT (MMTV-PymT)) showed increased numbers of tumor-associated B cells, mast cells, and CD31+ endothelial cells, which correlate with higher levels of vascular endothelial growth factor (VEGF) in the tumor and serum (Sevenich et al. 2011). These data suggest that cathepsin B facilitates increased immune cell infiltration and tumor angiogenesis.


Cathepsin B knockout mice are both viable and fertile and they do not reveal any distinguishing phenotypes from their wild-type counterparts (Deussing et al. 1998). However, in cathepsin B knockout mice under challenged conditions such as experimental pancreatitis, the premature and intracellular activation of trypsinogen that is followed by acinar cell necrosis is largely reduced in the absence of cathepsin B (Halangk et al. 2000). Deletion of the cathepsin B gene in mice reduces TNF-associated hepatocyte apoptosis, by inhibiting mitochondrial release of cytochrome c and caspase 9 and 3 activation and TNF-liver damage and animal mortality (Guicciardi et al. 2001). Excessive accumulation of saturated free fatty acids in liver cells directly induces mitochondrial dysfunction and oxidative stress. This stress was shown to be dependent upon lysosomal disruption and activation of cathepsin B in cathepsin B knockout mice (Li et al. 2008). In transgenic mice expressing human wt-APP, the knockout of cathepsin B significantly reduces the generation of brain Aβ and the APP-derived C-terminal β-secretase fragment, thus supporting the hypothesis that cathepsin B participates in Aβ production from APP containing the wt-β-secretase site (Hook et al. 2008). In a Rip-Tag-2 model, deletion of the cathepsin B gene reduces the frequency of initial angiogenic switching in dysplastic progenitors and impairs subsequent development of the tumor vasculature, leading to reduced tumor growth (Joyce et al. 2004). Moreover, null mutations in any one of the three cathepsins B, L, or S disrupts the progression of tumors to invasive carcinoma, indicating that each enzyme has an important, nonredundant role in the process of tumor invasion (Gocheva et al. 2006). On the contrary, mice deficient in both cathepsins B and L die shortly after birth with neuronal loss and severe brain atrophy (Felbor et al. 2002), an effect not observed in mice deficient in only cathepsin B or cathepsin L. Clearly these data indicate redundancy between the two enzymes in the maintenance of the central nervous system.

In transgenic mice that have been engineered to express human cathepsin B and have been crossed with transgenic MMTV-PymT mice, there is a 20-fold increase in cathepsin B activity in the mammary tumors (Sevenich et al. 2010). Although overexpression of human cathepsin B does not affect tumor onset, there is accelerated tumor growth with an increase in tumor weight and a decline in their histopathological grades. In addition, tumors from human cathepsin B overexpressing mice exhibit increased numbers of tumor-associated B cells, mast cells, and endothelial cells (Gomez-Auli et al. 2016; Sevenich et al. 2011). In human colon carcinomas, pericellular cathepsin B contributes significantly to tumor invasion and metastatic spread, whereas lysosomal cathepsin B promotes tumorigenesis and growth (Bian et al. 2016; Reinheckel et al. 2012), suggesting cathepsin B might be a good therapeutic target for colon carcinomas. Other studies have shown that the acidic microenvironment surrounding tumors increases the contribution of pericellular cathepsin B to tumor proteolysis and invasion (Robey et al. 2009; Rothberg et al. 2012, 2013).

Splice Variants

Although the mechanisms for regulating cathepsin B mRNA splicing remain unclear, cathepsin B variants can be subdivided into two subpopulations that give rise to two distinct translation products (Berquin et al. 1995, 2001; Gong et al. 1993; Mehtani et al. 1998). The first group of variants lack exon 2 [CB(-2)] and was originally observed in malignant tumors overexpressing cathepsin B (Gong et al. 1993). Although CB(-2) encodes for the same enzyme as the full-length CB transcript and its distribution is unaltered, its translation rate is doubled (Gong et al. 1993). This altered rate of translation and hence increased expression may augment pathologies including tumorigenesis (Gong et al. 1993) and osteoarthritis (Berardi et al. 2001). The second group lacks exons 2 and 3 [CB(-2,3)], thus translation starts at an initiation codon at position 53 within exon 4. This mRNA variant is translated into a naturally truncated form of cathepsin B (Δ51CB) that is not distributed to intracellular vesicles, i.e., endosomal/lysosomal compartments, and has no cathepsin B enzymatic activity (Baici et al. 2005; Muntener et al. 2004). Δ51CB is more prominently expressed in tumors (Mehtani et al. 1998) and arthritic tissues/cells (Berardi et al. 2001). Δ51CB is also found to be associated with the nucleus, the cytoplasmic side of intracellular membranes (Mehtani et al. 1998), and mitochondria (Muntener et al. 2004). Furthermore, its overexpression stimulates nuclear fragmentation and cell death (Bestvater et al. 2005; Muntener et al. 2003).

Antibodies and Activity-Based Probes

Several monoclonal and polyclonal antibodies to both human and murine cathepsin B are available both commercially and from individual laboratories. Antibodies are available that recognize all forms of cathepsin B (i.e., latent and mature), as well as others that recognize only epitopes within the propeptide (Weber et al. 2015). These antibodies detect cathepsin B in immunoblots and in both cultured cells and histological tissue sections.

A series of activity-based probes (ABPs) (e.g., GB123 and GB137) have been generated to detect active cysteine cathepsins B and L in vitro and in vivo (Blum et al. 2007). These probes contain a tag for visualization (e.g., Cy5 for GB123 and near-infrared fluorescence for GB137) and directly label the active protease through activity-dependent covalent modification. New generation ABPs (e.g., GB137) contain a quencher in close proximity to the tag to reduce nonspecific, fluorescent signals from unbound probes. Once the ABP is bound to the active site of the target enzyme, the quencher is released by the active enzyme and a fluorescent signal is generated. This reduces the background noise from unbound probes and allows for imaging of more defined proteolytic activity in live cells (reviewed in Dive et al. 2008; Edgington et al. 2011). ABPs that detect active cathepsin B as well as active cathepsins X, S, and L are being used in preclinical studies with the goal of translating them to clinical use for detection of early lesions (e.g., colon polyps by endoscopy (Sensarn et al. 2016) and fibrotic lesions of idiopathic pulmonary fibrosis by optical imaging and PET/CT (Withana et al. 2016)). Some success in translating ABPs to the clinic has been achieved for PET/CT scanning of idiopathic pulmonary fibrosis patients although the signal to noise ratios of current probes needs to be improved for them to be used routinely.


Cathepsin B is a hydrolytic enzyme that belongs to the family of cysteine cathepsins and is ubiquitously expressed in most cell and tissue types. Cathepsin B exhibits both endopeptidase and exopeptidase activities, which are modulated by a flexible occluding loop. The occluding loop blocks access to the active-site cleft of the enzyme thus favoring exopeptidase activity, whereas displacement of the occluding loop away from the active site allows for endopeptidase activity. Cathepsin B activity is regulated through the endogenous inhibitors of the cystatin superfamily. Localization of cathepsin B is predominantly to late endosomal/lysosomal compartments where it is primarily involved in processing and turnover of proteins. Cathepsin B is also found in other sites such as the cell surface where it degrades ECM proteins and activates extracellular proteolytic networks. Overexpression of cathepsin B is observed in a variety of pathologies, including in inflammatory immune cells that accelerate disease progression. This suggests that cathepsin B could be a therapeutic target and that ABPs for cathepsin B will be useful for both detecting disease and monitoring progression and responses to therapies.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Dora Cavallo-Medved
    • 1
    • 2
  • Bonnie F. Sloane
    • 1
    • 3
  • Kamiar Moin
    • 1
    • 3
  1. 1.Department of PharmacologyWayne State UniversityDetroitUSA
  2. 2.Department of Biological SciencesUniversity of WindsorWindsorCanada
  3. 3.Barbara Ann Karmanos Cancer InstituteWayne State UniversityDetroitUSA