Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1 alpha subunit, resulting from intratumoral hypoxia and genetic alterations, has been demonstrated in common human cancers and is correlated with tumor angiogenesis and patient mortality. Here we demonstrate that hypoxia or HIF-1 alpha overexpression stimulates Matrigel invasion by HCT116 human colon carcinoma cells, whereas this process is inhibited by a small interfering RNA directed against HIF-1 alpha. We show that HIF-1 regulates the expression of genes encoding cathepsin D; matrix metalloproteinase 2; urokinase plasminogen activator receptor (uPAR); fibronectin 1; keratins 14, 18, and 19; vimentin; transforming growth factor alpha; and autocrine motility factor, which are proteins that play established roles in the pathophysiology of invasion. Neutralizing antibodies against uPAR block tumor cell invasion induced by hypoxia or HIF-1 alpha overexpression. These results provide a molecular basis for promotion of the invasive cancer phenotype by hypoxia and/or HIF-1 alpha overexpression.
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PMID:Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. 1261 33

Up-regulation of S100P, a member of the S100 calcium-binding protein family, is an early molecular event in the development of pancreatic cancer and it is expressed at high levels in both precursor lesions and invasive cancer. To gain more insight into the molecular mechanisms underlying the functional roles of this protein, we stably overexpressed S100P in the Panc1 pancreatic cancer cell line and identified the consequent changes in global protein expression by two-dimensional difference in-gel electrophoresis. The observed changes in target proteins were confirmed by Western blot analysis and immunofluorescence, whereas their functional effect was investigated using motility and invasion assays. In this study, we have shown that overexpression of S100P led to changes in the expression levels of several cytoskeletal proteins, including cytokeratins 8, 18, and 19. We have also shown disorganization of the actin cytoskeleton network and changes in the phosphorylation status of the actin regulatory protein cofilin. Additionally, we have shown that overexpression of S100P leads to increased expression of another early pancreatic cancer marker, S100A6, as well as the aspartic protease cathepsin D, both of which are involved in cellular invasion. Functional studies showed that the increased invasive potential of S100P-overexpressing cells was at least partially due to the increase in cathepsin D expression. In summary, our data suggest that these changes could contribute to the metastatic spread of pancreatic cancer and may explain the devastating prognosis of this disease.
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PMID:The role of S100P in the invasion of pancreatic cancer cells is mediated through cytoskeletal changes and regulation of cathepsin D. 1787 3