The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

Small, D.; Burden, Roberta E.; Scott, Christopher J.

doi:10.1007/s12018-011-9095-5

Cited by 22 publications

(19 citation statements)

References 127 publications

(136 reference statements)

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“…As with many other protease species, the association of cathepsin S with a range of substrates and pathological conditions are increasingly being made (Small et al, 2011) (Figure 1). As tools such as genetic ablation models, chemical biology probes and substrates are developed, the role of cathepsin S in these diseases is being more comprehensively dissected, highlighting its potential as a therapeutic target.…”

Section: Cathepsin S and Diseasementioning

confidence: 99%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

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Cathepsin S is a member of the cysteine cathepsin protease family. It is a lysosomal protease which can promote degradation of damaged or unwanted proteins in the endo-lysosomal pathway. Additionally, it has more specific roles such as MHC class II antigen presentation, where it is important in the degradation of the invariant chain. Unsurprisingly, mis-regulation has implicated cathepsin S in a variety of pathological processes including arthritis, cancer, and cardiovascular disease, where it becomes secreted and can act on extracellular substrates. In comparison to many other cysteine cathepsin family members, cathepsin S has uniquely restricted tissue expression and is more stable at a neutral pH, which supports its involvement and importance in localised disease microenvironments. In this review, we examine the known involvement of cathepsin S in disease, particularly with respect to recent work indicating its role in mediating pain, diabetes, and cystic fibrosis. We provide an overview of current literature with regards cathepsin S as a therapeutic target, as well as its role and potential as a predictive diagnostic and/or prognostic marker in these diseases.

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Section: Cathepsin S and Diseasementioning

confidence: 99%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

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161

139

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“…This potent elastinolytic and collagenolytic enzyme is unique amongst the 11 human lysosomal cysteine cathepsins due to its ability to retain its activity in more neutral pH conditions, such as the extracellular environment . Consequently, CatS has been implicated in a number of disease states, where it is secreted and promotes the remodelling of extracellular matrix (ECM) components, especially in conditions such as rheumatoid arthritis, atherosclerosis and cancer …”

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confidence: 99%

“…3,4 Consequently, CatS has been implicated in a number of disease states, where it is secreted and promotes the remodelling of extracellular matrix (ECM) components, especially in conditions such as rheumatoid arthritis, atherosclerosis and cancer. [5][6][7][8][9][10] Clinically, the upregulation of CatS in tumors has been observed in prostate, gastric, colorectal and brain tumors. [11][12][13][14] Indeed, in astrocytomas, increased CatS levels correlate with advancing tumor grade and a poorer patient prognosis.…”

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confidence: 99%

Cathepsin S from both tumor and tumor‐associated cells promote cancer growth and neovascularization

Small

Burden

Jaworski³

et al. 2013

Intl Journal of Cancer

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Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-associated cell derived cathepsin S. The most significant impact on tumor development was obtained when the protease was depleted from both sources. Further characterization revealed that the loss of cathepsin S led to impaired tumor vascularization, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumor growth. Analysis of cell types showed that in addition to the tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumor-associated cells can positively contribute to developing tumors and highlight cathepsin S as a therapeutic target in cancer.Cathepsin S (CatS) is a cysteine protease, found abundantly in antigen presenting cells (APCs), where it is known to have key roles in MHC class II antigen processing and presentation.

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“…Under physiological conditions, CatS is a potent protease that degrades intracellular proteins engulfed by lysosomes and extracellular elements such as elastin, fibronectin, laminin, and collagens [ 3 ]. Apart from its role in protein degradation, it is crucial to the immune response because it degrades the invariant chain II, an essential step in major histocompatibility complex (MHC) class II antigen presentation [ 4 ]. The latest research has shown that the activity of CatS is regulated by gamma-interferon-inducible lysosomal thiol reductase in B cells [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Cathepsin S Produces Neuroprotective Effects after Traumatic Brain Injury in Mice

Ding

et al. 2013

Mediators of Inflammation

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Cathepsin S (CatS) is a cysteine protease normally present in lysosomes. It has long been regarded as an enzyme that is primarily involved in general protein degradation. More recently, mounting evidence has shown that it is involved in Alzheimer disease, seizures, age-related inflammatory processes, and neuropathic pain. In this study, we investigated the time course of CatS protein and mRNA expression and the cellular distribution of CatS in a mouse model of traumatic brain injury (TBI). To clarify the roles of CatS in TBI, we injected the mice intraventricularly with LHVS, a nonbrain penetrant, irreversible CatS inhibitor, and examined the effect on inflammation and neurobehavioral function. We found that expression of CatS was increased as early as 1 h after TBI at both protein and mRNA levels. The increased expression was detected in microglia and neurons. Inhibition of CatS significantly reduced the level of TBI-induced inflammatory factors in brain tissue and alleviated brain edema. Additionally, administration of LHVS led to a decrease in neuronal degeneration and improved neurobehavioral function. These results imply that CatS is involved in the secondary injury after TBI and provide a new perspective for preventing secondary injury after TBI.

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The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

Cited by 22 publications

References 127 publications

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Cathepsin S from both tumor and tumor‐associated cells promote cancer growth and neovascularization

Inhibition of Cathepsin S Produces Neuroprotective Effects after Traumatic Brain Injury in Mice

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