Cathepsin L increases invasion and migration of B16 melanoma

Yang, Zhen; Cox, James L.

doi:10.1186/1475-2867-7-8

Cited by 54 publications

(49 citation statements)

References 31 publications

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“…Heparin and SCCA-1 Combine to Inhibit Cancer Cell Linederived Proteolytic Activity-Overexpression of cathepsin L has been identified in many human malignancies, including melanomas and colorectal cancers (19,24,25), and there is also previous evidence that SCCA-1 and heparin can independently inhibit metastasis (14). We investigated if SCCA-1 can inhibit secreted cathepsin L-like activity from two invasive human cancer cell lines and if heparin can enhance this inhibition.…”

Section: Binding Of Heparin Quenches the Intrinsic Tryptophanmentioning

confidence: 99%

“…This may implicate the immune system in triggering SCCA-1 secretion in the allergic response and perhaps also during malignancy. Extracellular mammalian targets have not yet been characterized, but it is known that cysteine cathepsins are also up-regulated in many cancers, including malignant melanoma, where secreted cathepsins contribute to the breakdown of the extracellular matrix during metastasis (18,19).…”

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confidence: 99%

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Heparin Enhances Serpin Inhibition of the Cysteine Protease Cathepsin L

Higgins

Fox

Kowalski

et al. 2010

Journal of Biological Chemistry

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The glycosaminoglycan heparin is known to possess antimetastatic activity in experimental models and preclinical studies, but there is still uncertainty over its mechanism of action in this respect. As an anticoagulant, heparin enhances inhibition of thrombin by the serpin antithrombin III, but a similar cofactor role has not been previously investigated for proteases linked to metastasis. The squamous cell carcinoma antigens (serpins B3 and B4) are tumor-associated proteins that can inhibit papainlike cysteine proteases, including cathepsins L, K, and S. In this study, we show that SCCA-1 (B3) and SCCA-2 (B4) can bind heparin as demonstrated by affinity chromatography, native PAGE gel shifts, and intrinsic fluorescence quenching. Binding was specific for heparin and heparan sulfate but not other glycosaminoglycans. The presence of heparin accelerated inhibition of cathepsin L by both serpins, and in the case of SCCA-1, heparin increased the second order inhibition rate constant from 5.4 ؋ 10 5 to >10 8 , indicating a rate enhancement of at least 180-fold. A templating mechanism was shown, consistent with ternary complex formation. Furthermore, SCCA-1 inhibition of cathepsin L-like proteolytic activity secreted from breast and melanoma cancer cell lines was significantly enhanced by heparin. This is the first example of glycosaminoglycan enhancement of B-clade serpin activity and the first report of heparin acting as a cofactor in serpin cross-class inhibition of cysteine proteases. Most importantly, this finding raises the possibility that the anticancer properties of heparin may be due, at least partly, to enhanced inhibition of prometastatic proteases.

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Section: Binding Of Heparin Quenches the Intrinsic Tryptophanmentioning

confidence: 99%

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confidence: 99%

Heparin Enhances Serpin Inhibition of the Cysteine Protease Cathepsin L

Higgins

Fox

Kowalski

et al. 2010

Journal of Biological Chemistry

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“…Increased expression of the CTSs of the cysteine protease family, such as CTSL, correlates with invasion and migration of highly metastatic B16 melanoma cells. 26 Trypsin 1 and 2, serine protease 3 (PRSS1, 2, and 3), and MMP13 were preferentially expressed in UMC-11 but not in H835 cells. Trypsin is implicated in colorectal carcinogenesis and promotes growth and dissemination of various cancers.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide gene expression analysis of chemoresistant pulmonary carcinoid cells

Olszewski

Zeillinger

Geißler

et al. 2010

LCTT

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Purpose: Carcinoids are highly chemoresistant tumors associated with a dismal prognosis. This study involved a comparison of the genome-wide gene expression pattern of a chemoresistant and a chemosensitive pulmonary carcinoid cell line to reveal factors that contribute to the resistant phenotype. Materials and methods: Gene expression of UMC-11 chemoresistant carcinoid cells as assessed by 32 K microarray was compared with H835 chemosensitive carcinoid cells, and the genes that were differentially expressed and expected to be related to chemoresistance were selected. Results: Drug-resistant UMC-11 cells exhibited increased expression of transcripts known to confer resistance to different cytostatics such as P-glycoprotein, multidrug resistance-associated proteins 2 and 3, effectors of the glutathione detoxification and xenobiotics degradation pathways, and ion transporters including Na + /K + -adenosine triphosphatase. In addition, enhanced t ranscription of several S100 proteins, capable of suppressing apoptosis, regulation of topoisomerase I (topo I) expression by antisense transcripts from TOPO1 pseudogenes, and alterations of the cytoskeleton seem to contribute to the multidrug-resistant phenotype. A multitude of epidermal growth factor (EGF)-related and neuropeptide growth factors, overexpression of proteases, and appearance of aerobic glycolytic metabolism complement the malignant phenotype of the UMC-11 cells. Conclusion:The multidrug-resistant phenotype of the UMC-11 pulmonary carcinoid cell line seems to be mediated by classical efflux pumps, drug metabolization or conjugation systems, and, possibly, modulation of apoptotic cell death by S100 proteins and topo I expression by pseudogene transcripts. Autocrine or paracrine stimulation by a host of EGF-related and neuropeptide growth factors, as well as high metastatic potency indicated by increased expression of components of aerobic glycolysis and proteolytic enzymes, may furthermore account for the failure of therapeutic interventions.

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“…It is secreted from the cell under certain conditions (Collette et al, 2004). Cathepsin L has also been shown to contribute to tumor cell invasion (Yang and Cox, 2007), metastasis (Lah et al, 2006), and malignancy (Skrzydlewska et al, 2005). Urbich et al have reported that cathepsin L has a critical role in vasculogenesis by promoting the invasive activity of endothelial progenitor cells.…”

Section: Discussionmentioning

confidence: 99%