Matrix metalloproteinases mediate the metastatic phenotype ofTheileria annulata-transformed cells

Parasitology ◽  
1996 ◽  
Vol 113 (5) ◽  
pp. 449-455 ◽  
Author(s):  
R. E. Adamson ◽  
F. R. Hall
Keyword(s):  
Marked Reduction ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Transformed Cells ◽  
Pathological Features ◽  
Metastatic Phenotype ◽  
Infected Cells ◽  
Metalloproteinase 9 ◽  
Metalloproteinase Activity ◽  
Specific Inhibitors

SUMMARYTheileria annulatainfects and reversibly transforms bovine leucocytes. The parasite-transformed cells are immortalized, metastatic and express a number of metalloproteinases including matrix metalloproteinase 9 which they secrete. All the metalloproteinases observed on substrate gels are inhibited by tissue inhibitor of metalloproteinase 1 and 4 synthetic inhibitors BB94, GM6001, BRL29808AI and Ro31–4724. We have adapted anin vitroassay for metastatic behaviour that measures the ability of parasitized cells to cross reconstituted basement membrane, Matrigel™. Using this we demonstrated that macroschizont-infected cells are invasivein vitroand that their invasive properties can be almost eliminated by the same specific inhibitors of metalloproteinases as used in the substrate gels. This demonstrates that the metastatic behaviour of the infected cells is due in part to metalloproteinase activity and strongly suggests a role for the metalloproteinases we observed on gels. This is further supported by the fact that an attenuated vaccine line which shows much reduced metalloproteinase activity also exhibits a marked reduction in metastatic behaviour. We suggest that these metalloproteinases are virulence factors mediating some pathological features of the disease and their loss in the vaccine line could provide an explanation for attenuation.

scholarly journals Akt Interacts with Usutu Virus Polymerase, and Its Activity Modulates Viral Replication

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 244
Author(s):  
Laura Albentosa-González ◽  
Rosario Sabariegos ◽  
Armando Arias ◽  
Pilar Clemente-Casares ◽  
Antonio Mas
Keyword(s):  
Public Health ◽  
Confocal Microscopy ◽  
Viral Replication ◽  
Insufficient Data ◽  
Health Concerns ◽  
Usutu Virus ◽  
A Cell ◽  
Infected Cells ◽  
Specific Inhibitors

Usutu virus (USUV) is a flavivirus that mainly infects wild birds through the bite of Culex mosquitoes. Recent outbreaks have been associated with an increased number of cases in humans. Despite being a growing source of public health concerns, there is yet insufficient data on the virus or host cell targets for infection control. In this work we have investigated whether the cellular kinase Akt and USUV polymerase NS5 interact and co-localize in a cell. To this aim, we performed co-immunoprecipitation (Co-IP) assays, followed by confocal microscopy analyses. We further tested whether NS5 is a phosphorylation substrate of Akt in vitro. Finally, to examine its role in viral replication, we chemically silenced Akt with three inhibitors (MK-2206, honokiol and ipatasertib). We found that both proteins are localized (confocal) and pulled down (Co-IP) together when expressed in different cell lines, supporting the fact that they are interacting partners. This possibility was further sustained by data showing that NS5 is phosphorylated by Akt. Treatment of USUV-infected cells with Akt-specific inhibitors led to decreases in virus titers (>10-fold). Our results suggest an important role for Akt in virus replication and stimulate further investigations to examine the PI3K/Akt/mTOR pathway as an antiviral target.

Pravastatin increases the expression of the tissue inhibitor of matrix metalloproteinase-1 and the oncogeneBaxin human aortic abdominal aneurysms

2008 ◽  
Vol 86 (7) ◽  
pp. 431-437 ◽  
Author(s):  
Petra J. Mateos-Cáceres ◽  
Antonio J. López-Farré ◽  
Pilar C. Morata ◽  
Priscila Ramos-Mozo ◽  
Carlos Macaya ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Apoptotic Index ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Hmg Coa Reductase ◽  
Matrix Metalloproteinase 1 ◽  
Abdominal Aortic ◽  
Coa Reductase ◽  
Metalloproteinase 9

The effect of pravastatin on matrix metalloproteinase-9 (MMP-9) and the level of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 was studied in explants of human abdominal aortic aneurysm (AAA) obtained from 13 patients. The effect of pravastatin on the apoptotic status of human AAA explants was also examined. Total MMP-9 content did not differ in human AAA explants incubated in vitro in the presence or absence of pravastatin (10−6mol/L) for 48 h. TIMP-1 levels were significantly increased in pravastatin-incubated AAA explants, but TIMP-2 production was not modified by pravastatin. Western blot experiments showed that, whereas Bax expression was increased in pravastatin-incubated AAA explants, the expression of Bcl-2 was not modified. On the other hand, the ratio of the expression of Bax to Bcl-2, an apoptotic index, was not modified by pravastatin. In the human AAA explants, the increase in Bax expression, but not the increase in TIMP-1 expression elicited by pravastatin, was reversed by l-mevalonate, a downstream HMG-CoA reductase metabolite, suggesting that the expression of Bax and TIMP-1 followed HMG-CoA reductase-dependent and -independent pathways, respectively. In conclusion, pravastatin increases both TIMP-1 and Bax expression in human AAA explants without changes in either MMP-9 activity or the apoptotic status.

scholarly journals An Antiviral Peptide Inhibitor That Is Active against Picornavirus 2A Proteinases but Not Cellular Caspases

2006 ◽  
Vol 80 (19) ◽  
pp. 9619-9627 ◽  
Author(s):  
Luiza Deszcz ◽  
Regina Cencic ◽  
Carla Sousa ◽  
Ernst Kuechler ◽  
Tim Skern
Keyword(s):  
Initiation Factor ◽  
Caspase Inhibitor ◽  
Wild Type ◽  
Caspase 9 ◽  
General Caspase Inhibitor ◽  
Infected Cells ◽  
Antiviral Peptide ◽  
Specific Inhibitors

ABSTRACT The replication of many viruses is absolutely dependent on proteolytic cleavage. Infected cells also use this biological mechanism to induce programmed cell death in response to viral infection. Specific inhibitors for both viral and cellular proteases are therefore of vital importance. We have recently shown that the general caspase inhibitor zVAD.fmk inhibits not only caspases, but also the 2A pro of human rhinoviruses (HRVs) (L. Deszcz, J. Seipelt, E. Vassilieva, A. Roetzer, and E. Kuechler, FEBS Lett. 560:51-55, 2004). Here, we describe a derivative of zVAD.fmk that inhibits HRV2 2A pro but that has no effect on caspase 9. This gain in specificity was achieved by replacing the aspartic acid of zVAD.fmk with methionine to generate zVAM.fmk. Methionine was chosen because an oligopeptide with methionine at the P1 position was a much better substrate than an oligopeptide with an alanine residue, which is found at the P1 position of the wild-type HRV2 2A pro cleavage site. zVAM.fmk inhibits the replication of HRV type 2 (HRV2), HRV14, and HRV16. In contrast to zVAD.fmk, however, zVAM.fmk did not inhibit apoptosis induced by puromycin in HeLa cells. zVAM.fmk inhibited in vitro the intermolecular cleavage of eukaryotic initiation factor 4GI (eIF4GI) by HRV2 2A pro at nanomolar concentrations. However, much higher concentrations of zVAM.fmk were required to inhibit HRV14 2A pro cleavage of eIF4GI. In contrast, intramolecular self-processing of HRV14 2A pro was much more susceptible to inhibition by zVAM.fmk than that of HRV2 2A pro , suggesting that zVAM.fmk inhibits HRV2 and HRV14 replication by targeting different reactions of the same proteinase.

scholarly journals Differential Modulatory Effects of Clarithromycin on the Production of Cytokines by a Tumor

1999 ◽  
Vol 43 (11) ◽  
pp. 2787-2789 ◽  
Author(s):  
Kazuhiko Sassa ◽  
Yutaka Mizushima ◽  
Masashi Kobayashi
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Mammary Adenocarcinoma ◽  
Necrosis Factor Alpha ◽  
Adenocarcinoma Cells ◽  
The Matrix ◽  
Factor Alpha ◽  
Metalloproteinase 9

ABSTRACT In vitro treatment with clarithromycin inhibited the expression of the matrix metalloproteinase-9, transforming growth factor β, and tumor necrosis factor alpha genes in 13762NF rat mammary adenocarcinoma cells. Transient enhancement, rather than inhibition, was observed for the interleukin-6 gene, and no significant change was observed for the tissue inhibitor of metalloproteinase-2 gene. Such an effect was not observed for cefotiam or gentamicin.

Bifunctional inhibitors of urokinase and metalloproteinase-9 for cancer treatment - in silico evaluation

2018 ◽  
Vol 5 ◽  
pp. 6-11
Author(s):  
Shawn P. Brewer ◽  
Jerzy Jankun
Keyword(s):  
Proteolytic Activity ◽  
Cancer Progression ◽  
In Silico ◽  
Cancer Metastasis ◽  
Hybrid Molecules ◽  
Increased Activity ◽  
Metalloproteinase 9 ◽  
Specific Inhibitors

Matrix metalloproteinase-9 (MMP-9), and urokinase plasminogen activator (uPA) overexpression or/and increased activity are considered causative elements for cancer invasion and metastasis. These enzymes are degrading the extracellular matrix (ECM) providing space for cancer progression and cancer cell mobility. Process of angiogenesis, in which microvascular endothelial cells form blood vessels, requires local degradation of the underlying basal lamina to invade into the stroma proximal to cancer, and it strongly depends on the activity of MMP-9 and uPA as well. Malignant tumor invasion, cancer metastasis and angiogenesis have been documented as a fundamental factors in the morbidity and mortality among cancer patients, thus their inhibition can be exploit therapeutically. Numerous in vivo and in vitro studies have demonstrated that inhibition of proteolytic activity can reduce caner invasion, tumor size and limit angiogenesis. Consequently human clinical studies were designed inhibiting urokinase or MMPs, but these target specific inhibitors produce mix results. One of the possible explanation could be that cancers are overexpressing more than one enzyme simultaneously – for instance urokinase and MMPs. Thus upregulated net proteolytic activity should be normalized rather than trying to inhibit single proteolytic enzyme. Therefore, starting from specific inhibitors we have created - in silico - several hybrid molecules that could inhibit both uPA and MMP-9. The best hybrid (UI1xAGB) had theoretical affinities of Ki = 1.61-9 mol for MMP-9 and Ki = 1.36-9 mol for uPA. In the future each individual hybrid would need to be successfully synthesized and checked in the in vitro and in vivo analyses.

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