Generation and degradation of human endostatin proteins by various proteinases

Ferreras, Mercedes; Felbor, Ute; Lenhard, Thomas; Olsen, Bjørn R.; Delaissé, Jean‐Marie

doi:10.1016/s0014-5793(00)02249-3

Cited by 339 publications

(274 citation statements)

References 28 publications

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“…However, the pro-angiogenic role of MMPs has been challenged by the recent findings that some MMPs (MMP2/3/7/9/12/13/14/20) can process and generate angiogenesis inhibitors like angiostatin or endostatin to inhibit endothelial cell proliferation, migration, and angiogenesis. [38][39][40][41][42] The role of MMP19 in cancer is as controversial as for all other MMPs. MMP19 is up-regulated in astroglial tumor and melanoma 43,44 and reported to increase human keratinocyte cell proliferation, migration, and adhesion on type I collagen through the IGF-signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Chan

Lung

et al. 2011

Intl Journal of Cancer

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The association of Matrix metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelial cells of the nasopharynx. This cancer has a unique racial and geographic distribution with a high incidence in Southern China and Southeast Asia among the Southern Chinese population. 1 The etiology of NPC is believed to be multifactorial including dietary and

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Section: Discussionmentioning

confidence: 99%

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Chan

Lung

et al. 2011

Intl Journal of Cancer

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“…37 On the other hand, recent reports have demonstrated that the generation of endostatin, an inhibitor of angiogenesis and tumor growth, is catalyzed by proteolytic enzymes, including cathepsin L and matrix metalloproteases. 38,39 However, cathepsin L as well as cathepsin B has been implicated in malignant transformation, 40,41 metastatic tumor growth and poor prognosis. [42][43][44] In particular, secreted and membrane-associated cathepsins appear to play an important role in metastasis and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Multifunctional anti‐angiogenic activity of the cyclic peroxide ano‐2 with antitumor activity

Arakawa

Endo

Kimura

et al. 2002

Intl Journal of Cancer

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Our focus was to develop an anti-angiogenic drug possessing the inhibitory activity of urokinase-type plasminogen activator (u-PA) production. During preliminary screening, the effects of 13 ozonides on the inhibition of u-PA production in human fibrosarcoma HT-1080 cells and on the inhibition of angiogenesis on chicken embryonic chorioallantoic membranes were determined. Of the ozonides tested, 9 inhibited in vitro u-PA production of HT-1080 cells and 7 of these 9 exhibited strong anti-angiogenic activity. Interestingly, 6 of the 13 ozonides also inhibited cathepsin B activity. 1-Phenyl-1, 4-epoxy-1H,4H-naphtho[1,8-de][1, 2]dioxepin (ANO-2) potently inhibited cathepsin B (IC 50 ‫؍‬ 0.47 M) as well as u-PA production. Consequently, ANO-2 was selected for further study. ANO-2 inhibited tube formation by human umbilical vein endothelial cells cultured on Matrigel while exhibiting no cytotoxicity. Additionally, in vivo administration of ANO-2 inhibited angiogenesis induced by mouse Sarcoma-180 cells tested using the mouse dorsal air sac assay. Moreover, ANO-2 also suppressed primary tumor growth and reduced the number of pulmonary metastases caused by Lewis lung carcinoma cells in mice. These in vitro and in vivo activities indicate that ANO-2 has considerable potential as a new and potent anti-angiogenic drug that inhibits both u-PA production and enzymatic activity of cathepsins, indicating that ANO-2 may be a multifunctional inhibitor of angiogenesis.

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“…Endostatin, a 22-kDa fragment of collagen XVIII, is a member of a group of endogenous antiangiogenic proteins (O'Reilly et al, 1997) that are activated by proteolytic processing (Ferreras et al, 2000). In fact, the antiangiogenic activity of endostatin is speculated to be specifically mediated by the inhibition of endothelial cell adhesion, migration and proliferation, and induction of apoptosis (Dhanabal et al, 1999).…”

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confidence: 99%

Mechanism of Fibroblast‐Like Synoviocyte Apoptosis Induced by Recombinant Human Endostatin in Rats with Adjuvant Arthritis

Huang

Chen

et al. 2008

The Anatomical Record

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by pronounced synovial hyperplasia, in which there may be an imbalance between the growth and death of fibroblast-like synoviocytes (FLS). The present study was undertaken to examine the effect of recombinant human endostatin (rhEndostatin) on FLS apoptosis in experimental RA. Adjuvant arthritis (AA) was induced in male Sprague Dawley (SD) rats. Using cultured AA FLS obtained from these rats, the apoptosis process was measured by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) as well as Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) labeling methods. In addition, the expression levels of the Fas, c-jun, NFjB, and caspase-3 gene products in synovial tissues were quantified by quantitative real-time polymerase chain reaction (qPCR) and/or Western blotting assays. Our data revealed that rhEndostatin induced apoptosis in AA FLS. The number and signal density of TUNEL-positive cells were significantly increased in rats treated with rhEndostatin (2.5 mg/kg). The percentage of Annexin V-FITC-positive cells was 6.67% after treatment with rhEndostatin at 25 mg/mL for 48 hr, compared with only 3.32% among untreated control cells. There were significant increases in Fas mRNA, c-jun mRNA, c-Jun protein, and caspase-3 (p20) protein in AA synovial tissues treated with rhEndostatin (2.5 mg/kg), whereas no significant difference in NFjB expression was detected between treated and untreated tissues. These findings indicate that rhEndostatin has a therapeutic effect on RA by inducing FLS apoptosis, which is strongly associated with increased expression of Fas, c-jun, and caspase-3, but not NFjB.

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Generation and degradation of human endostatin proteins by various proteinases

Cited by 339 publications

References 28 publications

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Multifunctional anti‐angiogenic activity of the cyclic peroxide ano‐2 with antitumor activity

Mechanism of Fibroblast‐Like Synoviocyte Apoptosis Induced by Recombinant Human Endostatin in Rats with Adjuvant Arthritis

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