Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Snake venom metalloproteinases (SVMPs) are structurally and functionally similar to matrix metalloproteinases (MMPs). We have previously demonstrated that a SVMP, named gaminelysin, can induce endothelial cell apoptosis [Biochem J. 357 (2001) 719]. In this study, the action mechanism of graminelysin in causing endothelial cell apoptosis was further investigated. We showed that the apoptosis was initiated with cell shape change and extracellular matrix degradation and occurred before cell detachment. Cleaved forms of MMP-2 might act in concert with graminelysin to cause apoptosis. During apoptosis, adherens junctions, including VE-cadherin and beta- and gamma-catenin were cleaved and alpha-catenin was decreased. VE-cadherin and beta-catenin at cell periphery were decreased and the discontinuity in alignment was found as observed with immunofluorescence microscopy. This was accompanied with a diffuse beta-catenin staining in the cytoplasm and a decreased F-actin stress fibers in some rounded cells. The decrease of VE-cadherin and beta-catenin in Triton-insoluble fractions confirmed that the association of adherens junctions with actin cytoskeleton was altered during apoptosis. Graminelysin-induced cleavage in adherens junctions was paralleled with the changes in paracellular permeability. We also detected the activation of caspase-3 and the decrease of Bcl-2/Bax ratio during apoptosis. However, caspase inhibitors showed differential effects in blocking the cleavage of PARP, adherens junctions, and DNA fragmentation. Taken together, the data presented suggest that metalloproteinase can control cell fates via the degradation of matrix proteins, the change of cell shape, and the cleavage of adherens junctions.
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PMID:Activation of MMP-2, cleavage of matrix proteins, and adherens junctions during a snake venom metalloproteinase-induced endothelial cell apoptosis. 1287 66

We investigated the effects of FK228 on cell proliferation and apoptosis against human glioblastoma (GM) T98G, U251MG, and U87MG cells. Upon exposure to FK228, cell proliferation was inhibited, and apoptosis detected by the cleavage of CPP32 was induced. FK228 increased the expression levels of p21 (WAF-1) and of pro-apoptotic Bad protein in all GM cells. Furthermore, FK228 treatment also reduced the anti-apoptotic protein Bcl-xL in all GM cells and anti-apoptotic Bcl-2 in U87MG cells, thereby shifting the cellular equilibrium from life to death. An increased accumulation of histone H4 was detected in the p21 (WAF-1) promoter and the structural gene (exon 2) and the Bad structural gene (exon 2 and 3) upon treatment with FK228, as assessed by chromatin immunoprecipitation (ChIP) assay. Thus, the results indicated that an increased expression of p21 (WAF1) and Bad due to FK228 is regulated, at least in part, by the degree of acetylation of the gene-associated histone. We also found that FK228 inhibits cellular invasiveness and decreases MMP-2 activity. In addition, the growth of transplanted human GM m-3 cells into the subcutaneous tissue of hereditary athymic mice was significantly inhibited, and apoptosis was induced with FK228 treatment. The results suggested that FK228 might be useful in the treatment of human GM, although further studies will be needed.
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PMID:Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell proliferation of human glioblastoma cells in vitro and in vivo. 1502 82

Matrix metalloproteinases (MMPs) and cyclooxygenase (COX) enzymes play pivotal roles in the metastatic process of colorectal cancers. Inhibition of both MMPs and COX could be an attractive option for the inhibition of cell growth and invasion. Two human colorectal cancer cell lines, LS174T and HT29, were challenged with MMP inhibitor (doxycycline), selective COX-2 inhibitor (NS-398), or a combination of these agents to evaluate cancer cell proliferation and invasion. Dose-dependent growth inhibition was observed in both cell lines when they were treated with a single therapy. These effects were not related to MMP-2 or MMP-9 expression potential of the cell lines. Doxycycline (10 microg/mL) induced G(0)/G(1) arrest, and 20 microg/mL provoked annexin V positivity and up-regulated caspase-3 activity in HT29 cells. However, 20 microg/mL doxycycline caused no distinct apoptotic change in LS174T cells. Although MMP expression was not inhibited by 5 to 10 microg/mL doxycycline or 50 to 100 micromol/L NS-398, MMPs' activities were down-regulated by these concentrations. Cellular invasion was noticed in LS174T cells, but their capacity for invasion was diminished by these inhibitors. The antiproliferative and antiinvasive effects of the combination therapy were more pronounced. Doxycycline (5 microg/mL) with 50 micromol/L NS-398 inhibited cell proliferation and doxycycline (5 microg/mL) with 100 micromol/L NS-398 attenuated MMP expression and activity, as well as capacity for invasion, compared with single therapy. These data suggest that combination therapy consisting of an MMP inhibitor with a COX-2 inhibitor is an attractive approach to the treatment of colorectal cancers. The use of this treatment regimen for chemoprevention or treatment of colorectal cancers should be considered in future clinical trials.
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PMID:Doxycycline inhibits cell proliferation and invasive potential: combination therapy with cyclooxygenase-2 inhibitor in human colorectal cancer cells. 1508 79

Brown Norway (BN) and BN Katholiek (BN/Ka) rat strains are both susceptible to develop lesions in the internal elastic lamina (IEL) of the aorta. BN/Ka rats are characterized by a single point mutation in the kininogen gene leading to deficiency in high- and low-molecular-weight kininogen. Recently, a suggestive quantitative trait locus for lesions in the IEL of the abdominal aorta was identified in an F2 intercross between Dahl salt-sensitive (SS) and BN rats, implicating kininogen as a positional candidate gene. Therefore, BN and BN/Ka rat strains represent ideal model organisms with which to study the contribution of kininogen to the genetic predisposition to IEL lesion formation and to characterize the early events underlying vascular remodeling. Here we present data demonstrating that genetic kininogen deficiency promotes the formation of aneurysms in the abdominal aorta but not the development of atherosclerosis upon 12-wk treatment with an atherogenic diet. Aneurysm formation was associated with an enhanced elastolysis, increased expression of MMP-2 and MMP-3, downregulation of TIMP-4, and with FasL- and caspase-3-mediated apoptosis. Kininogen-deficient animals also featured changes in plasma cytokines compatible with apoptotic vascular damage, i.e., upregulation of IFN-gamma and downregulation of GM-CSF and IL-1beta. Finally, in response to atherogenic diet, kininogen-deficient animals developed an increase in HDL/total cholesterol index, pronounced fatty liver and heart degeneration, and lipid depositions in aortic media without atherosclerotic plaque formation. These findings suggest that genetic kininogen deficiency renders vascular tissue prone to aneurysmatic but not to atherosclerotic lesions.
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PMID:Genetic kininogen deficiency contributes to aortic aneurysm formation but not to atherosclerosis. 1523 17

Matrix metalloproteinases (MMPs) may contribute to the pathophysiology of cerebral ischemia by degrading matrix components in the neurovascular unit. In this study, the authors document a pathway by which MMPs interfere with cell-matrix interactions and trigger caspase-mediated cytotoxicity in brain endothelial cells. Hypoxia-reoxygenation induced endothelial cytotoxicity. Cytoprotection with zDEVD-fmk confirmed that cell death was partly caspase mediated. The temporal profile of caspase-3 activation was matched by elevations in MMP-2 and MMP-9. MMP inhibitors significantly decreased caspase-3 activation and reduced endothelial cell death. Degradation of matrix fibronectin confirmed the presence of extracellular proteolysis. Increasing integrin-linked kinase signaling with the beta1 integrin-activating antibody (8A2) ameliorated endothelial cytotoxicity. The results suggest that MMP-9 and MMP-2 contribute to caspase-mediated brain endothelial cell death after hypoxia-reoxygenation by disrupting cell-matrix interactions and homeostatic integrin signaling.
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PMID:Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. 1524 Nov 80

Activated protein C (APC) is a physiological serine protease that regulates blood clotting and inflammation. Keratinocytes are a major cell type of human skin and play a fundamental role in normal skin metabolism and cutaneous wound healing. In this study, we investigated the regulatory role of APC on the function of human primary cultured keratinocytes. In an in vitro wounding assay, APC accelerated wound closure which was due jointly to increased cell proliferation and migration. APC attenuated calcium-induced cell death via prevention of cell apoptosis, as indicated by a decrease in both active caspase-3 and morphologically apoptotic cells. APC dramatically enhanced the expression and activation of MMP-2 by keratinocytes, whilst having no effect on MMP-9. GM6001, a broad spectrum MMP inhibitor, abolished cell migration in a dose-dependent manner and delayed in vitro wound healing. APC also significantly increased the production of IL-6 and IL-8 and suppressed calcium- and LPS-stimulated NF-kappaB activity. These results demonstrate a central role for APC in promoting cell proliferation and migration, preventing apoptosis and increasing MMP-2 activity in cultured keratinocytes. This regulatory activity implicates APC as having potential to promote re-epithelialisation during wound healing.
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PMID:Activated protein C stimulates proliferation, migration and wound closure, inhibits apoptosis and upregulates MMP-2 activity in cultured human keratinocytes. 1530 79

Accumulation of oxidized extracellular matrix between endothelium and muscle is an important risk factor in the endothelium-myocytes uncoupling in congestive heart failure. Although ventricular remodeling is accompanied by increased matrix metalloproteinase (MMP)-9 activity, it is unclear whether MMP-9 plays a role in endothelial apoptosis in chronic volume overload congestive heart failure. We tested the hypothesis that, in chronic volume overload, myocardial dysfunction involves endocardial endothelial (EE) apoptosis in response to MMP-9 activation, extracellular matrix accumulation, and endothelium-myocytes uncoupling. Arteriovenous fistula (AVF) was created in control (FVB/NJ) and MMP-9 knockout (MMP-9KO; FVB.Cg-MMP9(tm1Tvu)/J) mice. Sham surgery was used as control. Mice were grouped as follows: wild type, n = 3 (sham control); MMP-9KO, n = 3 (sham); AVF, n = 3; and MMP-9KO + AVF (n = 3). Heart function was analyzed by M-mode and Doppler echocardiography, and with a pressure-tipped Millar catheter placed in the left ventricle of anesthetized mice 8 wk after AVF. Apoptosis was detected by measuring caspase-3, transferase-mediated dUTP nick-end labeling (TUNEL), and CD-31 by immunolabeling. Protease-activated receptors-1, connexin-43, and a disintegrin and MMP-12 (ADAM-12) expression were measured by Western blot analyses. MMP-2 and MMP-9 expression were measured by quantitative RT-PCR. Compared with control, AVF caused an increase in left ventricle end diastolic pressure and decrease in -dP/dt. In contrast, in the MMP-9KO + AVF group, these variables were changed toward control levels. Increased EE apoptosis (caspase-3 activation and TUNEL/CD-31 colabeling) in AVF mice was prevented in the MMP-9KO + AVF group. Protease-activated receptor-1, connexin-43, and ADAM-12 were induced in AVF. MMP-9 gene ablation ameliorated the induction. The results suggest that impaired cardiac function in volume overload is associated with EE apoptosis, cardiac remodeling, and endothelium-myocytes uncoupling in response to MMP-9 activation.
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PMID:Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice. 1608 21

In the present study, we determined the impact of 5 and 10 days of muscle deconditioning induced by hindlimb suspension (HS) on the ubiquitin-proteasome system of protein degradation and caspase enzyme activities in rat soleus muscles. A second goal was to determine whether activities of matrix metalloproteinase-2/9 (MMP-2/9) and urokinase-type/tissue-type plasminogen activator (PAs) were responsive to HS. As expected, HS led to a pronounced atrophy of soleus muscle. Level of ubiquitinated proteins, chymotrypsin-like activity of 20S proteasome, and Bcl-2-associated gene product-1 protein level were all transitory increased in response to 5 days of HS. These changes may thus potentially account for the decrease in muscle mass observed in response to 5 days of HS. Caspase-3 activity was significantly increased throughout the experimental period, whereas activities of caspase-6, another effector caspase, and caspase-9, the mitochondrial-dependent activator of both caspase-3 and -6, were only increased in response to 10 days of HS. This suggests that caspase-3 may be regulated through mitochondrial-independent and mitochondrial-dependent mechanisms in response to HS. Finally, MMP-2/9 activities remained unchanged, whereas PAs activities were increased after 5 days of HS. Overall, these data suggest that time-dependent regulation of intracellular and extracellular proteinases are important in setting the new phenotype of rat soleus muscle in response to HS.
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PMID:Regulation of ubiquitin-proteasome system, caspase enzyme activities, and extracellular proteinases in rat soleus muscle in response to unloading. 1733 80

Dysfunction in apoptosis has been suggested to play an important role in the development of a distant metastasis. The Bcl-2 gene plays a key role in the response to chemotherapeutic agents, and its upregulation protects the cells from apoptosis by inactivating the Bax proteins through heterodimerization of Bcl-2/Bax. However, there is no direct evidence showing that the upregulation of Bcl-2 increases the antiapoptotic effects against chemotherapeutic agents and is associated with the production of a distant metastasis. In this study, the role of Bcl-2 in the production of distant metastasis was investigated by examining the activity of caspase-3 and the expression of matrix metalloproteinases (MMPs) after transfecting the Bcl-2 gene into human renal cell carcinoma cells (SN12C). In addition, the production of a distant metastasis was examined in an orthotopic animal model. In vitro, the SN12C/smb2 cells were more resistant to doxorubicin (DXR) than the untreated parental cells. The IC50 of the SN12C/smb2 was 50% higher than that of the parental cells. In addition, the caspase-3 activity of the SN12C/smb2 cells was lower than that of the parental cells after the DXR treatment. On the other hand, there was no difference in the expression of MMP-2 and MMP-9 between the SN12C and SN12C/smb2 cell lines. However, the SN12C/smb2 cells had a higher metastatic potential than the parental cells in the orthotopic animal model. Unlike the results from the in vitro analysis, the expression of MMP-2 and MMP-9 in the kidney tumors produced by the SN12C/smb2 cells was higher than in the kidney tumors produced by the SN12C/vector. These results show that the upregulation of Bcl-2 in human renal cell carcinoma cells induces drug resistance to DXR. Moreover, Bcl-2 induced the expression of MMP in tumors grown in the orthotopic sites even though no appreciable effects were observed in the in vitro condition. When the in vitro and in vivo data were combined, it appears that the Bcl-2 gene initially affects the response to DXR. The cells that survive the DXR treatment then have a chance to become metastatic by increasing the levels of MMP in an orthotopic environment.
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PMID:Microenvironment effects on promoting upregulation of matrix metalloproteinases in Bcl-2-overexpressing renal cell carcinoma as a response to doxorubicin treatment inducing the production of metastasis. 1754 5

The aqueous extract of Psidium guajava L. (PE) inhibited the cancer cell DU-145 in a dose- and time-dependent manner. At 1.0 mg/mL, PE reduced the viability of PCa DU-145 (the androgen independent PCa cells) to 36.1 and 3.59%, respectively after 48 h and 72 h of incubations. The absolute cell viability suppressing capability (VSC)(AC) could reach 262.5 cells-mL-h/mg on exposure to PE for 72 h, corresponding to the safe ranges, i.e. the percent viability suppressing rates (PVSR) of 2.72 and 2.41 folds for DU-145 comparing to PZ-HPV-7 cells when treated with PE at 0.5 and 1.0 mg/mL respectively for 72 h. In addition, the colony forming capability of DU-145 cells was apparently lowered. The suppressing rates of which reached 8.09 and 5.96 colony/mg/day for D-145 and PZ-HPV-7 cells, respectively within the concentration range of PE at 0.1 asymptotically equal to 0.25 mg/mL. Cell cycle arrests at G0/G1 phase in both cells were observed by TUNEL assay and flow cytometric analysis, yet more prominently evident in DU-145. In addition, suppression of the matrix metalloproteinases MMP-2 and MMP-9, and the upregulation of active caspase-3 at 0.10 to 1.0 mg/mL in DU-145 were also effected in a dose-dependent manner by PE at 0.25 to 1.0 mg/mL, implicating a potent anti-metastasis power of PE. Conclusively, we ascribe the anticancer activity of PE to its extraordinarily high polyphenolic (165.61 +/- 10.39 mg/g) and flavonoid (82.85 +/- 0.22 mg/g) contents. Furthermore, PE might be useful for treatment of brain derived metastatic cancers such as DU-145, acting simultaneously as both a chemopreventive and a chemotherapeutic.
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PMID:Brain derived metastatic prostate cancer DU-145 cells are effectively inhibited in vitro by guava (Psidium gujava L.) leaf extracts. 1757 72


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