Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extent to which the BH3-only protein Bid is important for intrinsic (mitochondria-mediated) apoptotic cell death induced by genotoxic stress remains controversial. In the present study, we examine this issue using a panel of gene-manipulated Bax-deficient Jurkat T-lymphocytes. Cells stably depleted of Bid were far less sensitive than control-transfected cells to etoposide-induced apoptosis. In particular, drug-induced Bak activation, cytochrome c release, loss of mitochondrial membrane potential, and caspase activation were all decreased in cells lacking Bid. Reconstitution experiments using recombinant proteins and permeabilized Bid-deficient cells demonstrated that truncated Bid (tBid), but not full-length Bid, potently induced Bak activation and the release of cytochrome c. Further, caspase-8-deficient Jurkat cells efficiently cleaved Bid and were sensitive to drug-induced apoptosis. By comparison, Apaf-1-deficient cells, as well as cells overexpressing full-length X-linked inhibitor of apoptosis protein (XIAP) or the BIR1/BIR2 domains of XIAP, failed to cleave Bid in response to genotoxic stress. These data suggest that tBid plays an important regulatory role in the execution of DNA damage-induced cytochrome c release and apoptosis. However, the fact that cleavage of Bid to tBid is mediated by executioner caspases suggests that a self-amplifying feed forward loop involving caspases, Bid, and mitochondria may help determine irreversible commitment to apoptosis.
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PMID:Cleavage of Bid by executioner caspases mediates feed forward amplification of mitochondrial outer membrane permeabilization during genotoxic stress-induced apoptosis in Jurkat cells. 1923 49

Subtilase cytotoxin (SubAB) is an AB(5) cytotoxin produced by some strains of Shiga-toxigenic Escherichia coli. The A subunit is a subtilase-like serine protease and cleaves an endoplasmic reticulum chaperone, BiP, leading to transient inhibition of protein synthesis and cell cycle arrest at G(1) phase. Here we show that SubAB, but not the catalytically inactive mutant SubAB(S272A), induced apoptosis in Vero cells, as detected by DNA fragmentation and annexin V binding. SubAB induced activation of caspase-3, -7, and -8. Caspase-3 appeared earlier than caspase-8, and by use of specific caspase inhibitors, it was determined that caspase-3 may be upstream of caspase-8. A general caspase inhibitor blocked SubAB-induced apoptosis, detected by annexin V binding. SubAB also stimulated cytochrome c release from mitochondria, which was not suppressed by caspase inhibitors. In HeLa cells, Apaf-1 small interfering RNA inhibited caspase-3 activation, suggesting that cytochrome c might form an apoptosome, leading to activation of caspase-3. These data suggested that SubAB induced caspase-dependent apoptosis in Vero cells through mitochondrial membrane damage.
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PMID:Novel subtilase cytotoxin produced by Shiga-toxigenic Escherichia coli induces apoptosis in vero cells via mitochondrial membrane damage. 1938 Apr 66

(-)-Epigallocatechin-3-gallate (EGCG) is a major constituent of green tea and has been identified as an excellent anticancer agent. Nevertheless, there are no reports to date about the molecular mechanisms and signal pathways of EGCG on the induction of apoptosis in human adrenal NCI-H295 cancer cells. The purpose of this study was to investigate the anticancer effect and molecular mechanisms of EGCG on human adrenal NCI-H295 cancer cells. The results showed that EGCG induced growth inhibition in a dose- and time-dependent manner. Moreover, it exerted low cytotoxicity on Detroit 551 normal human embryonic skin cell. When NCI-H295 cells were treated with 20 microM EGCG, the mitochondrial membrane potential decreased and intracellular free Ca(2+) increased in a time-dependent manner as analysed by flow cytometry. EGCG decreased the protein levels of Bcl-2, Bcl-xl, xIAP, cIAP, Hsp70 and Hsp90, but increased the protein expression of Bad, Bax, Fas/CD95, cytochrome c, Apaf-1, AIF, GADD153, GRP78, and caspase-3, -7,-8 and -9 as observed by Western blotting examination. EGCG promoted caspase-8, -9 and -3 activities in a time-dependent manner. However, pretreatment of cells with inhibitors of caspase-8, -9 and -3 led to a decrease in caspase-8, -9 and -3 activities and an increase in the percentage of viable cells. Based on the above findings, it was confirmed that EGCG may be a drug candidate for the treatment of human adrenal cancer in the future.
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PMID:(-)-Epigallocatechin gallate induced apoptosis in human adrenal cancer NCI-H295 cells through caspase-dependent and caspase-independent pathway. 1941 99

Cholesterol secoaldehyde (ChSeco), a putative product of the reaction of ozone with cholesterol in aqueous environments, has been shown to induce apoptosis in H9c2 cardiomyoblasts. This study further investigated the involvement of apoptotic-related proteins and gene expression using RT-PCR, Western blot, and appropriate biochemical assays. The RT-PCR analysis revealed that ChSeco activates the expression of genes involved in the death receptor (extrinsic) pathway. The significance of this pathway was also evident from the increased activity of caspase-8. The overexpression of Apaf-1, loss of mitochondrial transmembrane potential, release of cytochrome c, and increased activity of caspase-9 provide further evidence for the involvement of a mitochondrial (intrinsic) pathway. Time-course analysis of ChSeco-exposed H9c2 cells showed an upstream increase in the generation of reactive oxygen species (ROS) and an associated decrease in the intracellular glutathione. N-acetyl-L-cysteine and Trolox significantly attenuated the ChSeco-induced ROS formation and cytotoxicity and also down-regulated the expression of the genes of all the players in either pathway. This study clearly shows that ChSeco induces apoptosis in H9c2 cells through ROS generation and the activation of both the intrinsic and the extrinsic pathway.
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PMID:Cholesterol secoaldehyde induces apoptosis in H9c2 cardiomyoblasts through reactive oxygen species involving mitochondrial and death receptor pathways. 1947 66

CWC-8 is a new synthesized novel 2-phenyl-4-quinolone compound in our laboratory which has demonstrated potential antitumor activity. In this study, we have defined the viability inhibition and apoptotic mechanisms of CWC-8 on human osteogenic sarcoma U-2 OS cells. According to the MTT assay, the cell viability was inhibited by CWC-8 in a dose- and time-dependent manner, with an IC(50) of 4.97+/-0.24 microM. CWC-8 treatment induced G(2)/M arrest and apoptosis in U-2 OS cells by cell cycle and flow cytometry analysis. It also profoundly caused a decrease in polymerized tubulin levels by in vitro tubulin polymerization assay which indicated that the microtubular cytoskeleton appears to be one of the cellular targets in response to CWC-8. Western blotting and CDK1 kinase assay showed that CWC-8 treatment caused a time-dependent increase of Cyclin B and CDK1 protein levels and activity during G(2)/M arrest. CWC-8 treatment also caused a time-dependent increase in Fas/CD95, FADD, cytosolic cytochrome c, caspase-8/-9/-3 active form, Apaf-1, AIF, Bax protein levels, and decrease in Bcl-2 protein level. CWC-8 also promoted caspase-8/-9 and -3 activities; however, pretreatment of cells with pan-caspase, caspase-8/-9 and -3 inhibitors led to reduced cell growth inhibition action. Taken together, these findings show CWC-8 could be a potential candidate for cancer therapy.
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PMID:Induction of mitotic arrest and apoptosis by a novel synthetic quinolone analogue, CWC-8, via intrinsic and extrinsic apoptotic pathways in human osteogenic sarcoma U-2 OS cells. 1966 27

ITR-284, a potent anti-leukemia agent of carboxamide derivative, has been shown to inhibit the proliferation of leukemia cells. In this study, the underlying molecular mechanisms in vitro and anti-leukemia activity in vivo of ITR-284 were investigated. ITR-284 reduced the cell viability and induced apoptosis in HL-60 and WEHI-3 leukemia cells. Following exposure of cells to 30 nM of ITR-284, there is a time-dependent decrease in the mitochondrial membrane potential (DeltaPsi(m)) and an increase in the reactive oxygen species (ROS). ITR-284 treatment also caused a time-dependent increase of Fas/CD95, cytosolic cytochrome c, cytosolic active form of caspase-8/-9/-3, cytosolic Apaf-1 and Bax, and the decrease of Bcl-2. However, the ITR-284-induced caspase-8/-9 and -3 activities can be blocked by pan-caspase inhibitor (Z-VAD-FMK). In addition, the anti-leukemia effects of ITR-284 in vivo were further evaluated in BALB/c mice inoculated with WEHI-3 cells. Orally treatment with ITR-284 (2 and 10mg/kg/alternate day for 7 times) increased the survival rate and prevented the loss of body weight in leukemia mice. The enlargement of spleen and infiltration of immature myeloblastic cells into spleen red pulp were significantly reduced in ITR-284-treated mice compared with control mice. Moreover, ITR-284 application can enhance the anti-leukemia effect of all-trans retinoic acid (ATRA). These results revealed that ITR-284 acted against both HL-60 and WEHI-3 in vitrovia both intrinsic and extrinsic apoptotic signaling pathways, and exhibited an anti-leukemic effect in a WEHI-3 orthotopic mice model of leukemia.
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PMID:Investigation of anti-leukemia molecular mechanism of ITR-284, a carboxamide analog, in leukemia cells and its effects in WEHI-3 leukemia mice. 1976 49

Apoptosis protease activating factor-1 (APAF-1), caspase-8 and caspase-9 are important factors in the execution of death signals. To study their prognostic influence in colon carcinoma, expression of APAF-1, caspase-8 and caspase-9 was determined by immunohistochemistry in normal colon mucosa (n = 8) and R0-resected stage II/III colon carcinomas (n >or= 124) using a semiquantitative score. Staining results were correlated with disease-free survival by Kaplan-Meier estimates, and multivariate Cox analyses were performed. In normal colon, APAF-1 and caspase-8 are most strongly expressed in the luminal surface epithelium, whereas caspase-9 is expressed all along the crypt axis. In colon carcinomas, there is considerable variability in the expression of these proapoptotic factors, although complete loss of caspase-8 and caspase-9 is rare. APAF-1 expression did not correlate with disease-free survival. Instead, both expression of caspase-9 and high-level expression of caspase-8 in a majority of tumor cells were significantly associated with adverse prognosis (p = 0.004 and p = 0.029, respectively). The influence of caspase-8 expression was mainly seen in patients with stage III colon carcinoma (p = 0.011), whereas the prognostic influence of caspase-9 expression was significant in stage II cases (p = 0.037) and just failed to be significant in stage III tumors (p = 0.0581). After adjusting for confounding factors in a multivariate Cox analysis, the effect of caspase-9 in predicting disease-free survival was confirmed (p = 0.003). Our data suggest that, in colon carcinomas, expression of caspase-8 and caspase-9 is significantly associated with poor survival. Caspase-9 may be an independent prognosticator in colon carcinoma.
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PMID:Expression and prognostic significance of APAF-1, caspase-8 and caspase-9 in stage II/III colon carcinoma: caspase-8 and caspase-9 is associated with poor prognosis. 2001 3

Ocimum gratissimum (OG) is widely used as a traditional herb for its antibacterial activity in Taiwan. Recently, antitumor effect of OG on breast cancer cell is also reported; however, the effects of OG on human pulmonary adenocarcinoma cell A549 remain unclear. Therefore, we aimed to investigate whether aqueous OG extract (OGE) affects viability of A549 cells and the signals induced by OGE in A549 cells. Cell viability assays revealed that OGE significantly and dose-dependently decreased the viability of A549 cell but not that of BEAS-2B cell. Morphological examination and DAPI staining indicated that OGE induced cell shrinkage and DNA condensation for A549 cells. Further investigation showed that OGE enhanced activation of caspase-3, caspase-9 and caspase-8 and increased protein level of Apaf-1 and Bak, but diminished the level of Bcl-2. Additionally, OGE inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) yet enhanced the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38). In conclusion, our findings indicate that OGE suppressed the cell viability of A549 cells, which may result from the activation of apoptotic signaling and the inhibition of anti-apoptotic signaling, suggesting that OGE might be beneficial to lung carcinoma treatment.
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PMID:Ocimum gratissimum Aqueous Extract Induces Apoptotic Signalling in Lung Adenocarcinoma Cell A549. 2095 89

Increased cell death of cardiomyocyte by oxidative stress is known to cause dysfunction of the heart. O. gratissimum is one of the more well-known medicinal plants among the Ocimum species and widely used in treatment of inflammatory diseases. In this study, we hypothesized that aqueous extract of O. gratissimum leaf (OGE) may protect myocardiac cell H9c2 from oxidative injury by hydrogen peroxide (H(2)O(2)). Our results revealed that OGE pretreatment dose-dependently protects H9c2 cells from cell death when exposed to H(2)O(2). Additionally, DNA condensation induced by H(2)O(2) was also reduced by OGE pretreatment, suggesting that Ocimum gratissimum extract may attenuate H(2)O(2)-induced chromosome damage. Further investigation showed that OGE pretreatment inhibited H(2)O(2)-induced activation of caspase-3 and caspase-9, as well as H(2)O(2)-induced upregulation of proapoptotic Apaf-1 and the release of cytosolic cytochrome c, but has little effect on the activation of caspase-8. Additionally, OGE pretreatment significantly upregulated Bcl-2 expression and Akt phosphorylation, and slightly affected the phosphorylation of mitogen-activated protein kinases including p38 MAPK and JNK. Taken together, our findings revealed that Ocimum gratissimum extract effectively inhibited the mitochondrial pathway and upregulated Bcl-2 expression, which may be important in protecting H9c2 cells from H(2)O(2)-induced cell death.
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PMID:Ocimum gratissimum Aqueous Extract Protects H9c2 Myocardiac Cells from H(2)O(2)-Induced Cell Apoptosis through Akt Signalling. 2095 36

Exposure of cells to hyperthermia is known to induce apoptosis, although the underlying mechanisms are only partially understood. Here, we examine the molecular requirements necessary for heat-induced apoptosis using genetically modified Jurkat T-lymphocytes. Cells stably overexpressing Bcl-2/Bcl-x(L) or stably depleted of Apaf-1 were completely resistant to heat-induced apoptosis, implicating the involvement of the mitochondria-mediated pathway. Pretreatment of wild-type cells with the cell-permeable biotinylated general caspase inhibitor b-VAD-fmk (biotin-Val-Ala-Asp(OMe)-CH(2)F) both inhibited heat-induced apoptosis and affinity-labeled activated initiator caspase-2, -8, and -9. Despite this finding, however, cells engineered to be deficient in caspase-8, caspase-2, or the caspase-2 adaptor protein RAIDD (receptor-interacting protein (RIP)-associated Ich-1/CED homologous protein with death domain) remained susceptible to heat-induced apoptosis. Additionally, b-VAD-fmk failed to label any activated initiator caspase in Apaf-1-deficient cells exposed to hyperthermia. Cells lacking Apaf-1 or the pro-apoptotic BH3-only protein Bid exhibited lower levels of heat-induced Bak activation, cytochrome c release, and loss of mitochondrial membrane potential, although cleavage of Bid to truncated Bid (tBid) occurred downstream of caspase-9 activation. Combined, the data suggest that caspase-9 is the critical initiator caspase activated during heat-induced apoptosis and that tBid may function to promote cytochrome c release during this process as part of a feed-forward amplification loop.
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PMID:Activation of caspase-9, but not caspase-2 or caspase-8, is essential for heat-induced apoptosis in Jurkat cells. 2097 29


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