Protein C inhibitor regulates both cathepsin L activity and cell-mediated tumor cell migration

Fortenberry, Yolanda M.; Brandal, Stephanie; Bialas, Ryan C.; Church, Frank C.

doi:10.1016/j.bbagen.2010.03.003

Cited by 16 publications

(10 citation statements)

References 56 publications

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“…How CTSL inhibition affects tumor cell migration is not nearly as clear. As was the case in our investigations (Fig 2), studies examining the effect of CTSL abrogation by RNA interference also have shown that CTSL inhibition can affect tumor cell migration [48, 49]. Although the mechanism by which CTSL promotes tumor cell migration has not been delineated, Reiser et al 2004 [50]; have shown that in nephrotic syndromes such as glomerular proteinuria, CTSL can enhance podocyte migration by promoting cell detachment and remodeling of extracellular matrix components while migration of normal podocytes was found to be independent of CTSL activity.…”

Section: Discussionsupporting

confidence: 81%

Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells

Sudhan

Siemann

2013

Clin Exp Metastasis

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Metastasis remains the major cause of therapeutic failure, poor prognosis and high mortality in breast and prostate cancer patients. Aberrant microenvironments including hypoxia and acidic pH are common features of most solid tumors that have been long associated with enhanced metastasis and poor patient outcomes. Novel approaches to reduce metastatic incidences and improve overall survival of cancer patients clearly are needed. The crucial role of Cathepsin L (CTSL) in the dissemination of tumor cells has led to the development of novel cathepsin L inhibition strategies. The present study evaluated the ability of KGP94, a small molecule inhibitor of CTSL, to impair the metastatic phenotype of prostate (PC-3ML) and breast (MDAMB- 231) cancer cells both under normal and aberrant microenvironmental conditions. To assess the role of CTSL in hypoxia and acidosis triggered metastasis associated cell functions, secreted CTSL levels were determined under conditions pertinent to the tumor microenvironment. Acute exposures to hypoxic or acidic conditions significantly elevated secreted CTSL levels either through an increase in intracellular CTSL levels or through activation of lysosomal exocytosis or both, depending on the tumor type. Increases in CTSL secretion closely paralleled enhanced tumor cell migration and invasion suggesting that CTSL could be an essential factor in tumor microenvironment triggered metastasis. Importantly, KGP94 treatment led to marked attenuation of tumor cell invasion and migration under both normal and aberrant microenvironmental conditions suggesting that it may have significant utility as an anti-metastatic agent.

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Section: Discussionsupporting

confidence: 81%

Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells

Sudhan

Siemann

2013

Clin Exp Metastasis

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“…Later, the inhibition of several other proteases, including the pancreatic enzymes trypsin and chymotrypsin, by PCI has been shown. [3]–[12]. Like other members of the serpin family, PCI acts as a suicide substrate for its target proteases.…”

Section: Introductionmentioning

confidence: 99%

Interaction of Protein C Inhibitor with the Type II Transmembrane Serine Protease Enteropeptidase

et al. 2012

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The serine protease inhibitor protein C inhibitor (PCI) is expressed in many human tissues and exhibits broad protease reactivity. PCI binds glycosaminoglycans and certain phospholipids, which modulate its inhibitory activity. Enteropeptidase (EP) is a type II transmembrane serine protease mainly found on the brush border membrane of epithelial cells in the duodenum, where it activates trypsinogen to initiate the digestion of food proteins. Some active EP is also present in duodenal fluid and has been made responsible for causing pancreatitis in case of duodeno-pancreatic reflux. Together with its substrate trypsinogen, EP is furthermore present in the epidermis and in some cancer cells. In this report, we show that PCI inhibited EP with an apparent 2nd order rate constant of 4.48×10 4 M −1 s −1 . Low molecular weight (LMWH) and unfractionated heparin (UFH) slightly reduced the inhibitory effect of PCI. The SI (stoichiometry of inhibition) value for the inhibition of EP by PCI was 10.8 in the absence and 17.9 in the presence of UFH (10 U/ml). By inhibiting trypsin, chymotrypsin, and additionally EP, PCI might play a role in the protection of the pancreas from autodigestion. Furthermore the interaction of PCI with EP may influence the regulation of epithelial differentiation.

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“…Importantly, SERPINA5 exerted anticancer activity preventing metastasis and angiogenesis in tumor cells and hence is considered to be a putative tumor-suppressor gene in different studies (1,7,8). In breast cancer cells, SERPINA5 was found to regulate tumor cell migration, in part by inhibiting cathepsin L (9). On the other hand, SERPINA5 limited cell migration by direct interaction with fibronectin and disruption of the fibronectin-integrin signalling pathway, as shown in hepatocellular carcinoma (10).…”

mentioning

confidence: 99%

Identification of CpG Sites of SERPINA5 Promoter with Opposite Methylation Patterns in Benign and Malignant Prostate Cells

Hagelgans

Jandeck

Friedemann

et al. 2017

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Protein C inhibitor regulates both cathepsin L activity and cell-mediated tumor cell migration

Cited by 16 publications

References 56 publications

Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells

Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells

Interaction of Protein C Inhibitor with the Type II Transmembrane Serine Protease Enteropeptidase

Identification of CpG Sites of SERPINA5 Promoter with Opposite Methylation Patterns in Benign and Malignant Prostate Cells

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