Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor growth requires proteolytic activity. As a consequence, protein breakdown products are present in the circulation of patients with cancer. Within the past decade a large number of proteolytic fragments have been identified that inhibit angiogenesis and tumor growth. The mechanism of action of these inhibitors is still poorly understood. We recently found that the effects of the angiogenesis inhibitor endostatin on endothelial cells is critically dependent on the presence of cross-beta structure, a structure also present in amyloidogenic polypeptides in plaques of patients with amyloidosis, such as Alzheimer disease. We also showed that cross-beta structure containing endostatin is a ligand for tissue-type plasminogen activator (tPA). We noted that many angiogenesis inhibitors stimulate tPA-mediated plasminogen activation. Because the presence of cross-beta structure is the common denominator in tPA-binding ligands, we hypothesize that these endogenous antiangiogenic proteolytic fragments share features with amyloidogenic polypeptides. We postulate that the cross-beta structural fold is present in these antiangiogenic polypeptide fragments and that this structure mediates the inhibitory effects. The hypothesis provides new insights in the potential mechanisms of these angiogenesis inhibitors and offers opportunities to improve their use.
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PMID:Do antiangiogenic protein fragments have amyloid properties? 1516 35

Concomitant antitumoral resistance (CAR), the phenomenon by which the growth of distant secondary tumor implants or metastases in some tumor-bearing hosts is inhibited by the presence of a primary tumor, has been previously ascribed to an antiangiogenic process. Here, we investigated vascular endothelial growth factor (VEGF) and endostatin serum levels in nude or BALB/c mice bearing human lung tumors (Calu-6 and H460) or murine mammary tumors (M3MC, M-234p and M-234m), respectively. In these experimental models we previously found an association between in vivo generation of CAR and in vitro conversion of plasminogen into angiostatin. Serum endostatin level in CAR+ Calu-6-bearing mice was significantly higher than in CAR- H460 counterpart. Sera from mammary tumor-bearing mice showed similar levels of endostatin, regardless of their ability to induce CAR. Conversely, serum VEGF levels in mice bearing CAR+ tumors were lower than those found in CAR- tumor-bearing hosts. Immunostaining with an anti-CD31 antibody revealed that secondary tumors subjected to CAR were significantly less vascularized than primary tumors, while this difference was not observed in CAR- tumors. In vitro studies showed an inhibitory effect of sera from CAR-inducing tumors on endothelial cell proliferation as compared to normal sera, whereas sera from non-CAR-inducing tumors did not alter endothelial proliferation and, in some instances, even caused stimulation of endothelial proliferation. These data suggest that the antiangiogenic mechanism operating in concomitant antitumoral resistance is the result of an increase in the ratio of antiangiogenic/proangiogenic regulators. The levels of the factors involved in this phenomenon can vary in the different tumor models, but the trend favoring the inhibition of angiogenesis is always conserved.
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PMID:Angiogenic and antiangiogenic balance regulates concomitant antitumoral resistance. 1516 35

Tetranectin is a plasminogen kringle 4 domain-binding protein present in plasma and various tissue locations. Decreased plasma tetranectin or increased tetranectin in stroma of cancers correlates with cancer progression and adverse prognosis. A possible mechanism through which tetranectin could influence cancer progression is by altering activities of plasminogen or the plasminogen fragment, angiostatin. Tetranectin was found to bind to the kringle 1-4 form of angiostatin (AST $;{\text{K1-4}}$ ). In addition, tetranectin inhibited binding of plasminogen or AST $;{\text{K1-4}}$ to extracellular matrix (ECM) deposited by endothelial cells. Finally, tetranectin partially counteracted the ability of AST $;{\text{K1-4}}$ to inhibit proliferation of endothelial cells. This latter effect of tetranectin was specific for AST $;{\text{K1-4}}$ since it did not counteract the antiproliferative activities of the kringle 1-3 form of angiostatin (AST $;{\text{K1-3}}$ ) or endostatin. These findings suggest that tetranectin may modulate angiogenesis through interactions with AST.
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PMID:Tetranectin Binds to the Kringle 1-4 Form of Angiostatin and Modifies Its Functional Activity. 1524 Sep 16

Angiogensis can be blocked by inhibitors such as endostatin and angiostatin. The kringle 5 fragment of plasminogen also has a potent inhibitory effect on endothelial cell proliferation and leads to the inhibition of angiogenesis. It has promise in anti-angiogenic therapy due to its small size and potent inhibitory effect. Preparation of kringle 5 has been achieved through the proteolysis of native plasminogen and recombinant DNA technology. Bacterially expressed recombinant kringle 5 is mainly insoluble and expressed at low level. The refolding yield is also low. To produce recombinant human kringle 5 in a large quantity, we have genetically modified a strain of Pichia pastoris. On methanol induction, this strain expressed and secreted biologically active, recombinant kringle 5. The expression level of the engineered strain in culture reached more than 300 mgl(-1). Purification was easily achieved by precipitation, hydrophobic and DEAE ion exchange chromatography. The recovery of recombinant kringle 5 was about 50% after purification. Yeast-expressed kringle 5 has a higher activity in anti-endothelial proliferation than bacterially expressed kringle 5.
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PMID:High level expression of kringle 5 fragment of plasminogen in Pichia pastoris. 1571 25

To investigate whether compromised angiogenesis could contribute to the impaired healing of venous leg ulcers, we have analyzed fluids from venous leg ulcers for the presence of the angiogenesis inhibitors angiostatin and endostatin. Multiple fragments related to angiostatin were detected by Western blot analysis. One angiostatin fragment was identified by mass spectrometry as plasminogen kringle domains 1-3 containing amino acids 82-343 of plasminogen, and a fraction containing this fragment inhibited tubule formation of human umbilical vein endothelial cells in a Matrigel assay. The leg ulcer fluids also contained endogenous endostatin (20 kDa) as well as higher molecular weight endostatin-related proteins. The concentrations of endostatin in the wound fluids, which ranged from 12.8 to 65.5 ng/ml, were higher than the concentration in human serum (7.7 ng/ml). Most of the endostatin in leg ulcer fluid appeared to be bound to the proteoglycan glypican-1. These data suggest that anti-angiogenic activity is present at the site of venous leg ulcers, and at least in the case of angiostatin, is biologically active.
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PMID:Multiple fragments related to angiostatin and endostatin in fluid from venous leg ulcers. 1582 39

Several anti-angiogenic factors are derived from proteolytic processing of large molecules including endostatin from type XVIII collagen and angiostatin from plasminogen. In previous studies we showed that neostatin-7, the C-terminal 28kDa endostatin-spanning proteolytic fragment, is generated from the proteolytic action of matrix metalloproteinase matrilysin (MMP)-7 on type XVIII collagen. Now, we report a second member of the neostatin family of proteins, neostatin-14. Given the small quantities of neostatin-7 and -14 generated by the breakdown of naturally occurring collagen XVIII (using MMP-7 and -14, respectively), we used two other approaches to characterize the anti-angiogenic properties of these molecules: murine recombinant neostatin in vitro, and gene therapy. We demonstrate that murine recombinant neostatin-7 inhibits calf pulmonary artery endothelial cell proliferation and that microinjection of neostatin-7 and neostatin-14 naked DNA into the corneal stroma of mice results in significant reduction of basic fibroblast growth factor-induced corneal neovascularization. These results provide supportive evidence of the possible anti-angiogenic effect of neostatins.
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PMID:Functional characterization of neostatins, the MMP-derived, enzymatic cleavage products of type XVIII collagen. 1597 92

Angiostatin, a proteolytic fragment of plasminogen, is a potent angiogenesis inhibitor able to suppress tumor growth and metastasis through inhibition of endothelial cell proliferation and migration. Previously, we showed that angiostatin binds and inhibits F(1)F(o) ATP synthase on the endothelial cell surface and that anti-ATP synthase antibodies reduce endothelial cell proliferation. ATP synthase also occurs on the extracellular surface of a variety of cancer cells, where its function is as yet unknown. Here, we report that ATP synthase is present and active on the tumor cell surface, and angiostatin, or antibody directed against the catalytic beta-subunit of ATP synthase, inhibits the activity of the synthase. We show that tumor cell surface ATP synthase is more active at low extracellular pH (pH(e)). Low pH(e) is a unique characteristic of the tumor microenvironment. Although the mechanism of action of angiostatin has not been fully elucidated, angiostatin treatment in combination with acidosis decreases the intracellular pH (pH(i)) of endothelial cells, leading to cell death. We also find that, at low pH(e), angiostatin and anti-beta-subunit antibody induce intracellular acidification of A549 cells, as well as a direct cytotoxicity that is absent in tumor cells with low levels of extracellular ATP synthase. These results establish angiostatin as an antitumorigenic and antiangiogenic agent through a mechanism implicating tumor cell surface ATP synthase. Furthermore, these data provide evidence that extracellular ATP synthase plays a role in regulating pH(i) in cells challenged by acidosis.
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PMID:Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase. 1642 20

Angiogenesis, the process by which new blood vessels are formed is critical for embryonic development and physiological functioning of normal tissues. Angiogenesis also plays a critical role in the pathology of many diseases including cancer, wherein the supply and demand for blood vessels determines the rate of cancer growth. A number of therapeutic strategies are being developed to inhibit pathological angiogenesis. Kringle domains of plasminogen such as kringle 5 (K5) and a proteolytic fragment of collagen type XVIII (endostatin) are well-characterized, potent angiogenesis inhibitors. These inhibitors activate different intracellular signaling pathways to induce apoptosis and inhibit cell proliferation. Recent studies from our group have shown that K5 and endostatin can also induce autophagy in addition to apoptosis in endothelial cells. A common feature of the two treatments was the upregulation of Beclin 1 levels leading to alterations in the Beclin 1-Bcl-2 complex. Angiogenesis inhibitor-induced autophagy in endothelial cells was independent of nutritional or hypoxic stress and initiated even in the presence of endothelial-specific survival factors such as vascular endothelial growth factor (VEGF). Interfering with the autophagic response by knocking down Beclin 1 levels dramatically increased apoptosis of endothelial cells. These findings identify the autophagic response as a novel target for enhancing the therapeutic efficacy of angiogenesis inhibitors.
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PMID:Autophagy and angiogenesis inhibition. 1764 71

Coronary artery disease (CAD) is the leading cause of mortality in diabetic patients. Because of the diffuse nature of their disease, diabetic patients may be at risk for incomplete revascularization, highlighting a potential role for proangiogenic therapy in this group. This study investigates molecular mechanisms of angiogenesis in diabetic patients. Myocardial tissue was harvested from patients undergoing coronary artery bypass grafting [nondiabetic (ND) 11, type 2 diabetic (DM) 10]. Expression of angiostatin, endostatin, their precursors (plasminogen and collagen XVIII, respectively), enzymes leading to their production [matrix metalloprotease (MMP)-2 and -9, cathepsin L], and an inhibitor of MMPs (tissue inhibitor of metalloproteinase) was assessed with Western blotting. MMP activity was assessed. Coronary collateralization was graded by Rentrop scoring of angiograms. Plasminogen and collagen XVIII expression were similar between groups. Angiostatin expression trended to increase 1.24-fold (P = 0.07), and endostatin expression increased 2.02-fold in DM patients relative to ND (P = 0.02). MMP-9 expression was no different between groups, whereas MMP-2 expression decreased 1.8-fold in diabetics (P = 0.003). MMP-2 and -9 activity decreased 1.33-fold (P = 0.03) and 1.57-fold (P = 0.04), respectively, in diabetic patients. Cathepsin L expression was 1.38-fold higher in diabetic patients (P = 0.02). Coronary collateralization scores were ND 2.1 +/- 0.37 vs. DM 1.0 +/- 0.4 (P = 0.05). Myocardial endostatin expression correlated strongly with the percentage of hemoglobin A(1c) (r = 0.742, P = 0.0001). Myocardial expression of angiostatin and endostatin demonstrated significant negative linear correlations with coronary collateralization (angiostatin r = -0.531, P = 0.035, endostatin r = -0.794, P = 0.0002). Diabetic patients with CAD exhibit increased levels of the antiangiogenic proteins angiostatin and endostatin and differential regulation of the enzymes governing their production relative to ND patients. Myocardial levels of these proteins show significant correlation to coronary collateralization. These findings offer potential new therapeutic targets for enhancing proangiogenic therapy and insight into the angiogenic impairments seen in diabetes.
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PMID:Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation. 1907 76

Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow-derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.
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PMID:Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins. 1971 80


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