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

Hypoxia-inducible factor (HIF)-1alpha is a crucial transcription factor involved in the adaptive response to hypoxia, whereas cathepsin D, which regulates angiostatin in several cancer cell lines, has been reported to be upregulated by HIF-1alpha. In order to determine the involvement of angiogenesis in pituitary adenomas, we studied the expression of both HIF-1alpha and cathepsin D in tissues from 58 patients (39 women, 19 men, ranging in age from 20 to 78 yr), sorted by histological group, and assayed by double immunohistochemistry. HIF-1alpha immunoreactivity, confined to the nucleoplasm, was present in both tumor and vascular endothelial cells. There was no difference in microvascular density (p = 0.7761) by histotype. ACTH-producing adenomas showed the lowest level of HIF-1alpha, whereas prolactin (PRL)-producing adenomas and HIF-1alpha-positive microvessels showed the highest (p < 0.001). In contrast, the lowest expression of cathepsin D was observed in PRL-producing adenomas, whereas the highest expression was detected in ACTH-producing adenomas (p < 0.0001). Imaging analysis with fluorescence double immunohistochemistry showed that HIF-1alpha-negative tumor cells did not express significantly higher levels of cathepsin D. In these poorly vascularized tumors, the hypoxic marker HIF-1alpha may not downregulate cathepsin D. The mechanisms of tumor angiogenesis and cell invasion in pituitary adenomas may differ from those in other tumor cells.
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PMID:Expression of hypoxia-inducible factor 1alpha and cathepsin D in pituitary adenomas. 1619 97

The fibulins are a family of secreted glycoproteins that are characterized by repeated epidermal-growth-factor-like domains and a unique C-terminus structure. Fibulins modulate cell morphology, growth, adhesion, and motility. Our initial basement membrane degradome screen using Cathepsin D, a tumor microenvironment-associated protease, contained fragments of fibulin-1 and full length fibulin-5. In this report, we evaluate the antiangiogenic activity of fibulin-1 and fibulin-5. Tumor studies demonstrate that both fibulin-1 and fibulin-5 suppress HT1080 tumor growth. CD31 labeling and TUNEL assay further reveal that fibulin-1 suppression of HT1080 tumor growth is associated with diminished angiogenesis and also enhanced apoptosis of endothelial cells and tumor cells. In contrast, fibulin-5 inhibits tumor angiogenesis with a minimal anti-apoptotic affect. Cathepsin D digestion of fibulin-1 produces a fragment with nearly the same molecular weight as fibulin-5, and this fragment (named Neostatin) inhibits endothelial cell proliferation. Additionally, degradation of basement membrane by cathepsin D liberates both fibulin-1 fragments and fibulin-5, which function to inhibit angiogenesis.
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PMID:Basement membrane derived fibulin-1 and fibulin-5 function as angiogenesis inhibitors and suppress tumor growth. 1822 70

The lysosomal aspartic protease cathepsin D (cath-D) is overexpressed and hyper-secreted by epithelial breast cancer cells. This protease is an independent marker of poor prognosis in breast cancer as it is correlated with the incidence of clinical metastasis. In normal cells, cath-D is localized in intracellular vesicles (lysosomes and endosomes). In cancer cells, overexpressed cath-D accumulates in cells, where it may affect their degradative capacities, and the pro-enzyme is hyper-secreted in the tumor micro-environment. In addition, during apoptosis, lysosomal cath-D is released into the cytosol, where it may interact with and/or cleave pro-apoptotic, anti-apoptotic, or nuclear proteins. Several studies have shown that cath-D affects various different steps in tumor progression and metastasis. Cath-D stimulates cancer cell growth in an autocrine manner, and also cath-D plays a crucial paracrine role in the tumor micro-environment by stimulating fibroblast outgrowth and tumor angiogenesis. A mutant D231N-cath-D, which is devoid of catalytic activity, remained mitogenic, indicating an additional action of cath-D by protein-protein interaction. Targeting cath-D in cancer may require the use of inhibitors of its catalytic activity, but also the development of new tools to inhibit its protein binding functions. Thus, elucidation of the mechanism of action of cath-D is crucial if an appropriate strategy is to be developed to target this protease in cancer. The discovery of new physiological substrates of cath-D using proteomic approaches can be expected to generate new critical targets. The aim of this review is to describe the roles of the cath-D protease in cancer progression and metastasis, as well as its function in apoptosis, and to discuss how it can be targeted in cancer by inhibiting its proteolytic activity and/or its binding protein activity.
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PMID:Pathophysiological functions of cathepsin D: Targeting its catalytic activity versus its protein binding activity? 2049 20