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Cysteine cathepsins

multifunctional enzymes in cancer

Key Points

  • There are 11 human cysteine cathepsins, which primarily function as endopeptidases within endolysosomal compartments. Specific cysteine cathepsins have extracellular functions, for example, cathepsin K in bone remodelling by osteoclasts.

  • Multiple mechanisms increase cysteine cathepsin expression in tumours, including amplification of the cathepsin B gene and alternative splicing of cathepsin L and B transcripts. Increases in expression occur both in tumour cells and tumour-associated cells such as macrophages, endothelial cells and myoepithelial cells.

  • In tumours these enzymes can be secreted, bind to specific regions on the cell membrane and are localized in endolysosomal vesicles. Their substrates and functions differ depending on their location.

  • Causal roles for cysteine cathepsins in cancer have been demonstrated by pharmacological and genetic techniques. This includes functional downregulation of cysteine cathepsin activity by increasing expression of endogenous inhibitors and administration of small-molecule cysteine protease inhibitors.

  • Causal roles for cysteine cathepsins in cancer have also been identified in regard to intracellular matrix degradation following endocytosis of collagens by urokinase plasminogen activator receptor-associated protein (uPARAP).

  • Causal roles for specific cysteine cathepsins in cancer have been demonstrated by downregulating their expression or crossing mouse models of cancer with mice in which the cysteine cathepsin has been genetically ablated. These studies have identified roles for cysteine cathepsins in both tumour cells and tumour-associated cells such as endothelial cells and macrophages.

Abstract

Cysteine cathepsins are highly upregulated in a wide variety of cancers by mechanisms ranging from gene amplification to post-transcriptional modification. Their localization within intracellular lysosomes often changes during neoplastic progression, resulting in secretion of both inactive and active forms and association with binding partners on the tumour cell surface. Secreted, cell-surface and intracellular cysteine cathepsins function in proteolytic pathways that increase neoplastic progression. Direct proof for causal roles in tumour growth, migration, invasion, angiogenesis and metastasis has been shown by downregulating or ablating the expression of individual cysteine cathepsins in tumour cells and in transgenic mouse models of human cancer.

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Figure 1: The cysteine cathepsins that are known to be expressed in tumour cells and tumour-associated cells, and have been identified as contributing to neoplastic progression.
Figure 2: The localization of cysteine cathepsins on the tumour cell membrane might be mediated through an association of individual cysteine cathepsins with binding partners in membrane microdomains.
Figure 3: Differential localization of cathepsin B in migrating and stationary MCF-7 human breast carcinoma cells.
Figure 4: Intracellular degradation of cysteine cathepsins in lysosomes.

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Acknowledgements

We acknowledge all the scientists who made contributions to the research reviewed here but who were not cited owing to space limitations. We acknowledge with special gratitude the contributions of M. Sameni and D. Cavallo-Medved, K. Moin, I. Podgorski, and D. R. Schwartz to this review. Microscopy was carried out in the Microscopy and Imaging Resources Laboratory of Wayne State University, supported in part by the US National Cancer Institute, National Institute of Environmental Health Sciences and National Technology Center for Networks and Pathways of the National Institutes of Health. The authors are supported by an Avon Foundation American Association for Cancer Research International Scholar Award in Breast Cancer Research (M.M.M.), the National Cancer Institute, the National Technology Center for Networks and Pathways of the National Institutes of Health, and a Department of Defense Breast Cancer Center of Excellence grant.

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Papillon-Lefevre syndrome

FURTHER INFORMATION

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The Proteolysis Map

Glossary

Papillon–Lefevre syndrome

A rare genetic disorder that is due to mutation of cathepsin C, and is characterized by severe destructive periodontal inflammation and skin lesions.

Pycnodysostosis

A rare genetic disorder that is due to mutation of cathepsin K, which is characterized by short stature and abnormally dense brittle bones.

Alu element

A short interspersed repeated DNA element of 300 bp in length that comprises 5% of the human genome. It includes a site that is recognized by the restriction enzyme AluI.

CpG island

A short stretch of DNA with a high frequency of phosphodiester-linked cytosine and guanine pairs. CpG islands are often located near and within promoters of frequently expressed genes, including housekeeping genes.

Caveolae

A subset of lipid rafts, which are flask-shaped invaginations of plasma membrane containing the structural protein caveolin.

Lipid raft

A cholesterol-rich region or domain in the plasma membrane.

Tetraspanin

Conserved proteins with four transmembrane domains that associate laterally with one another and with partner proteins in dynamic multimolecular complexes in the plasma membrane, to form what is termed the tetraspanin web.

Podosome

A dynamic actin-rich cell-adhesion structure that is associated with invasion and proteases, and is regulated by tyrosine kinases including Src.

Invadopodia

Cell-surface protrusions that are associated with invasion, are sites of degradation of extracellular matrix, are rich in proteases and are regulated by tyrosine kinases.

Annexin II

A member of a protein family that binds calcium and phospholipids. It exists as a monomer or heterotetramer with two molecules of S100A10 and is involved in plasminogen activation.

Focal adhesions

Dynamic contacts that serve as a primary site of cell attachment to underlying matrices and bridging using transmembrane integrins to the actin cytoskeleton and signalling pathways.

Angiogenic switch

A term designating the transition of an in situ tumour to an angiogenic phenotype accompanied by formation of new blood vessels and invasion of surrounding tissues.

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Mohamed, M., Sloane, B. multifunctional enzymes in cancer. Nat Rev Cancer 6, 764–775 (2006). https://doi.org/10.1038/nrc1949

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