The cystatin superfamily constitutes a large group of evolutionary related proteins that have various biological functions. It comprises three major families: type-1 cystatins, which are cytosolic andinclude A and B stefins; type-2 cystatins, which are present in most body fluids and include C, D, E, F, and S; and type-3 cystatins, which are present in plasma and include kininogens and fetuin.
Collectively, these molecules inactivate cystein-proteases (cathepsins) and regulate (a) bone resorption, neutrophil chemotaxis, and tissue inflammation, (b) hormone processing and antigen presentation, and (c) resistance to bacterial and viral infections. Cathepsins are involved in processing and presentation of antigens, as well as several pathological conditions such as inflammation, cancer, and neurodegeneration.Cystatin-C (CystC) is a low molecular weight, ubiquitously expressed, secretory protein, which regulates bone reabsorption, neutrophil chemotaxis, and the inflammatory response, among other functions.With regards to cancer, it has been clinically shown that CystC is downregulated in tumor cells from patients with different types of cancer.
The anti-tumor activity of CystC is due to its inhibitory effect on cathepsin B, and by acting as a TGF-beta antagonist.CystC inactivates cathepsin B, a cystein-protease involved in the activation of tumor invasion and metastasis. By inhibiting cathepsin B, CystC blocks the degradation of the extracellular matrix that facilitates cell invasion and migration. Through the highly conserved cystein-protease inhibitor domain, CystC binds to and inactivates cathepsin B, by forming a reversible, high-affinity enzyme-inhibitor complex.
In addition, Cyst-C antagonises TGF-beta binding to its receptor II (TGFbeta-RII). Cyst-C blocks TGF-beta signaling in endothelial cells, blocking angiogenesis, as well as signaling in tumor cells, inhibiting tumor growth and metastasis.
Cystatin C Antagonizes Transforming Growth Factor β Signaling in Normal and Cancer Cells. Sokol J. and Schiemann W. Molecular Cancer Research 2004; 2(3):183-195
The use of cystatin C to inhibit epithelial-mesenchymal transition and morphological transformation stimulated by transforming growth factor-beta. Sokol J. et al. Breast Cancer Research 2005; 7(5):R844-R853
Preclinical efficacy of cystatin C to target the oncogenic activity of transforming growth factor β in breast cancer. Tian M. and Schiemann W. Translational Oncology 2009; 2(3):174-183