Activity-based Protein Profiling Implicates Urokinase Activation as a Key Step in Human Fibrosarcoma Intravasation

Madsen, Mark A.; Deryugina, Elena I.; Niessen, Sherry; Cravatt, Benjamin F.; Quigley, James P.

doi:10.1074/jbc.m601223200

Cited by 45 publications

(37 citation statements)

References 46 publications

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“…After inhibition of uPA by natural or synthetic inhibitors in the chorioallantoic membrane of chick embryos, both inhibitors reduced intravasation and metastasis. The authors suggest uPA activation as a key step in tumour progression (Madsen et al, 2006). The effects of members of the uPA system on tumour cell biology, cell migration and metastases can be reversed in in vivo models.…”

Section: Discussionmentioning

confidence: 99%

Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

et al. 2010

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BACKGROUND: The urokinase plasminogen activator (uPA) system is one of the best-investigated protease systems, both under physiological and pathological conditions, including various types of cancer. However, effects of co-expression of members of the uPA system in soft-tissue sarcoma (STS) patients at the protein level in both tumour tissue and serum have not been investigated yet. METHODS: We examined 82 STS patients for protein levels of uPA, PAI-1and uPAR in tumour tissue and serum by ELISA. RESULTS: A significant correlation between high antigen levels of uPA, PAI-1 or uPAR in tumour tissue, and of uPAR in serum, with poor outcome of STS patients was found for the first time. Most strikingly, we observed an additive effect of combined uPA, PAI-1 or uPAR levels in tumour tissue extracts with uPAR levels in serum on patients' prognosis. High uPA/uPAR, PAI-1/uPAR and uPAR/ uPAR antigen levels in tumour tissue/serum were associated with a 5.9-fold, 5.8-fold and 6.2-fold increased risk of tumour-related death (P ¼ 0.003, 0.001 and 0.002, respectively) compared with those patients who displayed low levels of the respective marker combination. CONCLUSION: As expression of members of the uPA system in tumour tissue and serum is additively correlated with prognosis of STS patients, our results suggest that combinations of these biomarkers can identify STS patients with a higher risk of tumour-related death.

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Section: Discussionmentioning

confidence: 99%

Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

et al. 2010

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“…The activity level of the serine protease urokinase-type plasminogen activator (uPA) was substantially elevated in the high intravasating (HT-hi/diss) variants of the human fibrosarcoma cell line HT-1080. Inhibition of uPA activity significantly reduced the rate of intravasation and metastasis of HT-hi/diss cells, suggesting that active uPA is a key determinant of these processes [20].…”

Section: Profiling and Discovery Of Enzymes Involved In Cancermentioning

confidence: 96%

“…A set of enzymes, including KIAA1363, with elevated activities in the most aggressive tumor tissues were identified as potential breast cancer biomarkers. Recently, both FP-rhodamine and FPbiotin were used to identify enzymes that are involved in cancer cell intravasation, the process by which tumor cells enter into the vasculature [20]. The activity level of the serine protease urokinase-type plasminogen activator (uPA) was substantially elevated in the high intravasating (HT-hi/diss) variants of the human fibrosarcoma cell line HT-1080.…”

Section: Profiling and Discovery Of Enzymes Involved In Cancermentioning

confidence: 99%

Application of activity-based probes to the study of enzymes involved in cancer progression

Paulick

Bogyo

2008

Current Opinion in Genetics & Development

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SummaryMany tumor cells have elevated levels of hydrolytic and proteolytic enzymes, presumably to aid in key processes such as angiogenesis, cancer cell invasion, and metastasis. Since the activities of these enzymes are often regulated by post-translational mechanisms, their functional roles in cancer progression are difficult to study using traditional genomic and proteomic methods. Thus, methods that allow for the direct monitoring of enzyme activity in a physiologically relevant environment are required to better understand the roles of specific players in the complex process of tumorigenesis. This review highlights advances in the field of activity-based proteomics, which uses small molecules known as activity-based probes (ABPs) that covalently bind to the catalytic site of target enzymes. We discuss the application of ABPs to cancer biology, specifically to the discovery of tumor biomarkers, the screening of enzyme inhibitors, and the imaging of enzymes implicated in cancer.

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“…functional proteomics | activity profiling | pancreatic cancer TGF-β signaling S erine hydrolases are central effectors of the proliferative, invasive, and migratory properties of tumors, with roles in growth factor activation, extracellular matrix degradation, and angiogenesis (1)(2)(3)(4). Serine hydrolase transcript and protein levels are elevated in many cancer cell lines and primary tumors, but the functional relevance of these changes remains unknown (3,5).…”

mentioning

confidence: 99%

“…Recent studies have demonstrated that serine hydrolase ABPP permits the classification of human cancer lines into functional subtypes on the basis of tissue of origin and state of invasiveness (3). Moreover, this approach has identified tumor-associated activities with roles in cell invasion, migration, and intravasation (1,3,4).…”

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confidence: 99%

RBBP9: A tumor-associated serine hydrolase activity required for pancreatic neoplasia

Shields

Niessen²,

Murphy³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic cancer is one of the most lethal malignancies. To discover functionally relevant modulators of pancreatic neoplasia, we performed activity-based proteomic profiling on primary human ductal adenocarcinomas. Here, we identify retinoblastoma-binding protein 9 (RBBP9) as a tumor-associated serine hydrolase that displays elevated activity in pancreatic carcinomas. Whereas RBBP9 is expressed in normal and malignant tissues at similar levels, its elevated activity in tumor cells promotes anchorage-independent growth in vitro as well as pancreatic carcinogenesis in vivo. At the molecular level, RBBP9 activity overcomes TGF-β-mediated antiproliferative signaling by reducing Smad2/3 phosphorylation, a previously unknown role for a serine hydrolase in cancer biology. Conversely, loss of endogenous RBBP9 or expression of mutationally inactive RBBP9 leads to elevated Smad2/3 phosphorylation, implicating this serine hydrolase as an essential suppressor of TGF-β signaling. Finally, RBBP9-mediated suppression of TGF-β signaling is required for E-cadherin expression as loss of the serine hydrolase activity leads to a reduction in E-cadherin levels and a concomitant decrease in the integrity of tumor cell-cell junctions. These data not only define a previously uncharacterized serine hydrolase activity associated with epithelial neoplasia, but also demonstrate the potential benefit of functional proteomics in the identification of new therapeutic targets.functional proteomics | activity profiling | pancreatic cancer TGF-β signaling

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Activity-based Protein Profiling Implicates Urokinase Activation as a Key Step in Human Fibrosarcoma Intravasation

Cited by 45 publications

References 46 publications

Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

Co-detection of members of the urokinase plasminogen activator system in tumour tissue and serum correlates with a poor prognosis for soft-tissue sarcoma patients

Application of activity-based probes to the study of enzymes involved in cancer progression

RBBP9: A tumor-associated serine hydrolase activity required for pancreatic neoplasia

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