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Cell Death Dis. 2013 Dec 19;4:e974. doi: 10.1038/cddis.2013.485.

Cystatin SN neutralizes the inhibitory effect of cystatin C on cathepsin B activity.

Author information

1
Biomedical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
2
Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
3
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea.
4
Department of Life Science, Sookmyung Women's University, Seoul, Republic of Korea.
5
Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.

Abstract

Cystatin SN (CST1) is one of the several salivary cystatins that form tight equimolar complexes with cysteine proteases, such as the cathepsins. High expression of CST1 is correlated with advanced pTNM stage in gastric cancer. However, the functional role of CST1 in tumorigenesis has not been elucidated. In this study, we showed that CST1 was highly expressed in colon tumor tissues, compared with nontumor regions. Increased cell proliferation and invasiveness were observed in HCT116 cell lines stably transfected with CST1 cDNA (HCT116-CST1) but not in CST3-transfected cells. We also demonstrated that CST1-overexpressing cell lines exhibited increased tumor growth as well as metastasis in a xenograft nude mouse model. Interestingly, CST1 interacted with cystatin C (CST3), a potent cathepsin B (CTSB) inhibitor, with a higher affinity than the interaction between CST3 and CTSB in the extracellular space of HCT116 cells. CTSB-mediated cellular invasiveness and proteolytic activities were strongly inhibited by CST3, but in the presence of CST1 CTSB activities recovered significantly. Furthermore, domain mapping of CST1 showed that the disulfide-bonded conformation, or conserved folding, of CST1 is important for its secretion and for the neutralization of CST3 activity. These results suggest that CST1 upregulation might be involved in colorectal tumorigenesis and acts by neutralizing the inhibition of CTSB proteolytic activity by CST3.

PMID:
24357805
PMCID:
PMC3877556
DOI:
10.1038/cddis.2013.485
[Indexed for MEDLINE]
Free PMC Article

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