UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigated the effect of arctigenin (ARG) on the induction of apoptosis and the putative pathways of its action in HL-60 and K562 cells. MTT assay was used to detect the cytotoxic effect of ARG in HL-60 and K562 cells. The apoptosis was observed by Hoechst 33258 fluorescence staining and DNA agarose gel electrophoresis. Caspase-3 enzyme activity was measured by caspase-3 enzyme activity detection kit. The expression of related protein was analyzed by Western blotting and the vascular endothelial growth factor (VEGF) level was determined by enzyme-linked immunosorbent assay (ELISA). ARG-treated HL-60 cells and K562 cells exhibited growth inhibition and displayed several features of apoptosis, including DNA fragmentation and DNA laddering by agarose gel electrophoresis. It was observed that poly-(ADP-ribose) polymeras (PARP) were cleaved to smaller molecules and ARG induced upregulation of bax and downregulation of bcl-2 protein expression. However, it had no effect on VEGF levels. Taken together, this study demonstrated that ARG is a potent inducer of apoptosis and this was accompanied by caspase-3 activation and upregulation of bax/bcl-2, which offers a potential mechanism for the apoptosis-inducing activity of ARG.
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PMID:[Induction of apoptosis of the human leukemia cells by arctigenin and its mechanism of action]. 1871 45

Semaphorin 3B (SEMA3B), located at 3p21.3, is a secreted member of the semaphorin family important in axonal guidance. SEMA3B undergoes allele and expression loss in lung and breast cancer and can function as a tumor suppressor. Previously, we found that SEMA3B induces apoptosis in tumor cells either by reexpression or when applied as a soluble ligand. SEMA3B-induced apoptosis was mediated, in part, by blocking vascular endothelial growth factor autocrine activity in tumor cells. In the current study, treatment of lung and breast cancer cells with picomolar concentrations of soluble SEMA3B inhibited their growth; induced apoptosis; and was associated with decreased Akt phosphorylation, increase in cytochrome c release and caspase-3 cleavage, as well as increased phosphorylation of several proapoptotic proteins, including glycogen synthase kinase-3beta, FKHR, and MDM-2. Lung and breast cancer lines resistant to SEMA3B did not show these signaling changes and a tumor-derived missense SEMA3B mutant was inactive in this regard, providing specificity. SEMA3B-mediated inhibition of proliferation and induction of apoptosis in cancer cells were blocked by expressing a constitutively active Akt mutant and are linked to tumor cell expression of neuropilin-1 (Np-1). SEMA3B-insensitive Np-1-negative tumor cells acquired sensitivity to SEMA3B after forced expression of Np-1, whereas SEMA3B-sensitive Np-1-positive tumor cells lost sensitivity to SEMA3B after knockdown of Np-1 by small interfering RNA. We conclude that SEMA3B is a potential tumor suppressor that induces apoptosis in SEMA3B-inactivated tumor cells through the Np-1 receptor by inactivating the Akt signaling pathway. CA118384
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PMID:Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. 1892 1

We have identified a natural compound that activates apoptosis of epithelial cancer cells through activation of tumor necrosis factor-alpha (TNF-alpha), TNF receptor (TNFR)-associated death domain (TRADD), and caspases. The molecule 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde (HDNC, marmelin) was isolated and characterized from ethyl acetate fraction of extracts of Aegle marmelos. HDNC treatment inhibited the growth of HCT-116 colon cancer tumor xenografts in vivo. Immunostaining for CD31 showed that there was a significant reduction in microvessels in the HDNC-treated animals, coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA. Using hexoseaminidase assay, we determined that HDNC inhibits proliferation of HCT-116 colon and HEp-2 alveolar epithelial carcinoma cells. Furthermore, the cancer cells showed increased levels of activated caspase-3 and induced G(1) cell cycle arrest, which was suppressed by caspase-3 inhibitors. HDNC induced TNF-alpha, TNFR1, and TRADD mRNA and protein expression. Moreover, caspase-8 and Bid activation, and cytochrome c release, were observed, suggesting the existence of a cross-talk between death receptor and the mitochondrial pathways. HDNC inhibited AKT and extracellular signal-regulated kinase phosphorylation both in cells in culture and in tumor xenografts. In addition, electrophoretic mobility shift assay and luciferase reporter assays showed that HDNC significantly suppressed TNF-alpha-mediated activation and translocation of nuclear factor-kappaB (NF-kappaB). This was further confirmed by Western blot analysis of nuclear extracts wherein levels of RelA, the p65 component of NF-kappaB, were significantly less in cells treated with HDNC. Together, the data suggest that the novel compound HDNC (marmelin) is a potent anticancer agent that induces apoptosis during G(1) phase of the cell cycle and could be a potential chemotherapeutic candidate.
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PMID:Activation of apoptosis by 1-hydroxy-5,7-dimethoxy-2-naphthalene-carboxaldehyde, a novel compound from Aegle marmelos. 1892 33

Matrix Metalloproteinase-9 (MMP-9) consists of a prodomain, catalytic domain with 3 fibronectin-like type II modules and C-terminal hemopexin-like (PEX) domain. These domains play distinct roles in terms of proteolytic activity, substrate binding and interaction with inhibitors and receptors. To assess the potential of the MMP-9-PEX domain to interfere with tumor progression, we stably transfected human glioblastoma cells with an expression vector containing a cDNA sequence of the MMP-9-PEX. The selected clones exhibited decreased MMP-9 activity and reduced invasive capacity. We assessed how secretion of MMP-9-PEX by glioblastoma cells affects angiogenic capabilities of human microvascular endothelial cells (HMECs) in vitro. MMP-9-PEX conditioned medium treatment caused a reduction in migration of HMECs and inhibited capillary-like structure formation in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level. The suppression of HMECs survival by conditioned medium from MMP-9-PEX stable transfectants was associated with apoptosis induction characterized by an increase in cells with a sub-G0/G1 content, fragmentation of DNA, caspase-3, -8 and -9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. A significant tumor growth inhibition was observed in intracranial implants of MMP-9-PEX stable transfectants in nude mice with attenuation of CD31 and MMP-9 protein expression. These results demonstrate that MMP-9-PEX inhibits angiogenic features of endothelial cells and retards intracranial glioblastoma growth.
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PMID:The hemopexin domain of MMP-9 inhibits angiogenesis and retards the growth of intracranial glioblastoma xenograft in nude mice. 1894 17

Retinoic acids (RAs), which are active metabolites of vitamin A, are known to enhance Th2-type immune responses in vitro, but the role of RAs in allergic inflammatory cells remains unclear. In this study, we demonstrated that purified peripheral blood eosinophils expressed nuclear receptors for RAs at the mRNA and protein levels. Eosinophils cultured with all-trans RA (ATRA) and 9-cis-RA showed dramatically induced cell survival and nuclear hypersegmentation, and the efficacy of RAs (10(-6)M) was similar to that of IL-5 (1 ng/ml), the most critical cytokine for eosinophil activation. Pharmacological manipulation with receptor-specific agonists and antagonists indicated that the antiapoptotic effect of RAs was mediated through ligand-dependent activation of both retinoid acid receptors and retinoid X receptors (mainly retinoid acid receptors). Furthermore, using a gene microarray and a cytokine Ab array, we discovered that RAs induced vascular endothelial growth factor, M-CSF, and MCP-1 secretion, although they were not involved in eosinophil survival. RA-induced eosinophil survival appears to be associated with down-regulation of caspase 3 and inhibition of its enzymatic activity. These findings indicate an important role of RAs in homeostasis of granulocytes and provide further insight into the cellular and molecular pathogenesis of allergic reactions.
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PMID:Retinoic acids are potent inhibitors of spontaneous human eosinophil apoptosis. 1901 57

Tumor hypoxia has been reported to be a negative prognostic factor in a number of tumor sites, which suggests a positive correlation between tumor hypoxia and increased metastatic efficiency. Evidence shows that vascular endothelial growth factor (VEGF) stimulates angiogenesis in tumor growth and mediates neuroprotection to prevent an apoptotic cell death. Human neuroblastoma cells (CHP126) were exposed to moderate hypoxia for different time spans to explore the molecular stress responses. Apoptotic features as an increase of Bax/Bcl-2 ratio and activation of caspase 3 were observed at early period of exposure time, but these effects were reversed with the extension of hypoxic treatment. Hypoxia also activated MAPKs signaling pathways in a time-relative manner, which were involved in the regulation of hypoxia-related resistance of CHP126 cells. Meanwhile, VEGF and its receptor KDR were found to interact with MAPKs signaling pathways except the effect of hypoxia. Furthermore, rhVEGF(165) was utilized to discern that VEGF increased Bcl-2 and procaspase 3 expressions, contributing to a synergistic relationship of an angiogenic response with Bcl-2 in hypoxia via a cross talk, while the activation of ERK MAPK is important for both productions. These altered signals may be critical to predict a poor outcome; therefore, our knowledge provides new insight into apoptosis and angiogenesis control of tumor cells and suggests a strategy based on the blockade of hypoxia-induced VEGF signaling under hypoxia in neuroblastoma.
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PMID:VEGF and Bcl-2 interact via MAPKs signaling pathway in the response to hypoxia in neuroblastoma. 1904 66

Ex vivo gene transfer can improve the outcome of islet transplantation for treating type I diabetes. Earlier we have shown coexpression of human vascular endothelial growth factor (hVEGF) and human interleukin-1 receptor antagonist (hIL-1Ra) after transfection of plasmid DNA encoding these two genes. Due to poor transfection efficiency of plasmid DNA and the better known islet transduction efficiency of adenoviral (Adv) vectors, in this study, we constructed Adv-hVEGF-hIL-1Ra by cloning hVEGF and hIL-1Ra coding sequences and polyA signal under separate cytomegalovirus (CMV) promoters in Adenoquick plasmid (Ad 13.1). There was dose and time dependent expression of these genes after transduction of Adv-hVEGF-hIL1Ra into human islets. The mRNA expression of hVEGF and hIL-1Ra was more than 100 times higher than that of the nontransduced and bipartite plasmid transfected control islets. Transduced islets were viable as evidenced by insulin release upon glucose challenge. Coexpression of hVEGF and hIL-1Ra by islets showed decrease in caspase-3 activity and apoptosis induced by a cocktail of inflammatory cytokines such as TNF-alpha, IL-1beta and IFN-gamma. Compared to nontreated or Adv-LacZ transduced islets, transduction of islets with Adv-hVEGF-hIL-1Ra prior to transplantation under the kidney capsules of diabetic NOD-SCID mice reduced the blood glucose levels, and increased serum insulin and c-peptide levels. Immunohistochemical staining of the islet bearing kidney sections at day 20 after transplantation was positive for human insulin, hVEGF and von Willebrand factor. These results indicate that the bipartite Adv vector efficiently expresses both growth factor and antiapoptotic genes, decreases apoptosis and improves the outcome of islet transplantation.
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PMID:Bipartite vector encoding hVEGF and hIL-1Ra for ex vivo transduction into human islets. 1906 24

Human umbilical cord blood (HUCB) is a valuable source for cell therapy since it confers neuroprotection in stroke animal models. However, the responsible sub-populations remain to be established and the mechanisms involved are unknown. To explore HUCB neuroprotective properties in a PC12 cell-based ischemic neuronal model, we used an HUCB mononuclear-enriched population of collagen-adherent cells, which can be differentiated in vitro into a neuronal phenotype (HUCBNP). Upon co-culture with insulted-PC12 cells, HUCBNP conferred approximately 30% neuroprotection, as evaluated by decreased lactate dehydrogenase and caspase-3 activities. HUCBNP decreased by 95% the level of free radicals in the insulted-PC12 cells, in correlation with the appearance of antioxidants, as measured by changes in the oxidation-reduction potential of the medium using cyclic-voltammetry. An increased level of nerve growth factor (NGF), vascular endothelial growth factor and basic fibroblast growth factor in the co-culture medium was temporally correlated with a -medium neuroprotection effect, which was partially abolished by heat denaturation. HUCBNP-induced neuroprotection was correlated with changes in gene expression of these neurotrophic factors, while blocked by K252a, an antagonist of the TrkA/NGF receptor. These findings indicate that HUCBNP-induced neuroprotection involves antioxidant(s) and neurotrophic factors, which, by paracrine and/or autocrine interactions between the insulted-PC12 and the HUCBNP cells, conferred neuroprotection.
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PMID:Neuroprotection by cord blood neural progenitors involves antioxidants, neurotrophic and angiogenic factors. 1907 Jun 17

Liver fibrosis due to hepatic stellate cell (HSC) activation represents a common response to chronic liver injury. PTK787/ZK222584 (PTK/ZK) is a pan-VEGFR tyrosine kinase inhibitor. The aim of this study was to examine the effect of PTK/ZK in liver fibrosis. In primary HSCs, PTK/ZK inhibited the expression of alpha-smooth muscle actin (alpha-SMA), collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as cell proliferation, migration and actin filament formation. PTK/ZK-induced apoptosis of HSCs, which was correlated with increased caspase-3 activation and suppressed Bcl-2 expression. PTK/ZK also induced cell cycle arrest, accompanied by increasing the expression of p27(Kip1) and downregulation of cyclin D1 and cyclin E. PTK/ZK significantly inhibited vascular endothelial growth factor (VEGF) expression, as well as VEGF-simulated cell proliferation and phosphorylation of Akt in activated HSCs. In a murine fibrotic liver, PTK/ZK attenuated collagen deposition and alpha-SMA expression in carbon tetrachloride-induced fibrosis in both a 'prevention' and 'treatment' dosing scheme. These beneficial effects were associated with reduced phosphorylation of Akt and suppressed mRNA expression of procollagen-(I), TIMP-1, matrix metalloproteinase-9 and CD31. These findings provide novel insights into the potential value of blocking VEGF signaling by a small molecule tyrosine kinase inhibitor in treating hepatic fibrosis.
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PMID:PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling. 1911 84

This study investigated apoptotic mechanisms of down-expression vascular endothelial growth factor (VEGF) by short interfering RNA (siRNA) in human breast cancer MCF-7 cells. Human breast cancer cells were evaluated for the expression of VEGF and VEGF receptor 2 (VEGFR-2). siRNA targeting VEGF mRNA were chemically synthesized and transfected into cells with Lipofectamine2000. In vitro assessments were then made of the ability of anti-VEGF siRNA to knock down expression of VEGF and the subsequent effect this decreased expression had on breast cancer cell apoptosis. Growth curve construction and nude mice experimentation in vivo were performed to assess the effects of VEGF silencing on tumor growth. Those cells transfected with siRNA targeting VEGF showed a 65% knockdown in VEGF expression and a marked increase in cell apoptosis. The expression of Bcl-2 protein in MCF-7 cells was decreased, the level of Bax protein was kept the same, cytochrome c was released from mitochondria into cytosol, and the cleaved Caspase-3 protein rose after siRNA transfection. The siRNA targeting human VEGF could induce apoptosis in MCF-7 cells and the mechanism of apoptosis is possibly related with changing Bcl-2/Bax expression ratio, releasing cytochrome c from mitochondria into cytosol, and up-regulation of Caspase-3 protein, but also could suppress the growth of breast cancer cells in vivo. VEGF might be a potential therapeutic target for human breast cancer.
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PMID:The mechanisms on apoptosis by inhibiting VEGF expression in human breast cancer cells. 1916 40

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