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

The aim of our study was to characterize the temporal relationship of apoptosis to regional myocardial ischemia and reperfusion and we aimed to determine the effect of ischemia and reperfusion on the distribution of the pro-apoptotic cysteine protease caspase-3 (CPP 32, apopain, Yama) in an in vivo rat model. Male Sprague-Dawley rats (250-400 g) were anesthetized with sodium pentobarbital (65 mg/kg, i.p.), the left external carotid artery was isolated to monitor arterial pressure and a left thoracotomy was performed. Regional myocardial ischemia was induced by occluding the left main coronary artery for 45 min. The heart was reperfused for 0, 60, 120 or 180 min. TUNEL staining of formalin-fixed, paraffin-embedded left ventricle, and DNA fragmentation analysis, showed that apoptosis occurred during 45 min of ischemia alone, but further developed during the 3-h reperfusion period. Immunohistochemical analysis of ischemic/reperfused left ventricle showed caspase-3 levels were substantially elevated and localized in the ischemic/reperfused region, and that caspase-3 co-localized to TUNEL positive myocytes. Therefore, regional myocardial ischemia serves as a stimulus for myocyte apoptosis, and this form of cell death progresses time-dependently after the onset of reperfusion. Our studies implicate caspase-3 to be involved in apoptotic cell death in ischemic/reperfused rat heart.
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PMID:Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the rat. 960 22

The loss of cell volume is a fundamental feature of apoptosis. We have previously shown that DNA degradation and caspase activity occur only in cells which have shrunken as a result of potassium and sodium efflux (Bortner, C. D., Hughes, F. M., Jr., and Cidlowski, J. A. (1997) J. Biol. Chem. 272, 32436-32442). Furthermore, maintaining a normal intracellular potassium concentration represses the cell death process by inhibiting the activity of apoptotic nucleases and suppressing the activation of effector caspases (Hughes, F. M., Jr., Bortner, C. D. Purdy, G. D., and Cidlowski, J. A. (1997) J. Biol. Chem. 272, 30567-30576). We have now investigated the relationship between cell shrinkage, ion efflux, and changes in the mitochondrial membrane potential, in addition to the role of caspases in these apoptotic events. Treatment of Jurkat cells with a series of inducers which act via distinct signal transduction pathways, resulted in all of the cell death characteristics including loss of cell viability, cell shrinkage, K(+) efflux, altered mitochondrial membrane potential, and DNA fragmentation. Interestingly, only cells which shrunk had a loss of mitochondrial membrane potential and the other apoptotic characteristics. Treatment of Jurkat cells with an anti-Fas antibody in the presence of the general caspase inhibitor z-VAD, abrogated these features. In contrast, when Jurkat cells were treated with either the calcium ionophore A23187 or thapsigargin, z-VAD failed to prevent cell shrinkage, K(+) efflux, or changes in the mitochondrial membrane potential, while effectively inhibiting DNA degradation. Treatment of Jurkat cells with various apoptotic agents in the presence of either the caspase-3 inhibitor DEVD, or the caspase-8 inhibitor IETD also blocked DNA degradation, but failed to prevent other characteristics of apoptosis. Together these data suggest that the cell shrinkage, K(+) efflux, and changes in the mitochondrial membrane potential are tightly coupled, but occur independent of DNA degradation, and can be largely caspase independent depending on the particular signal transduction pathway.
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PMID:Caspase independent/dependent regulation of K(+), cell shrinkage, and mitochondrial membrane potential during lymphocyte apoptosis. 1041 18

Apoptosis induction may be a mechanism mediating the anticancer activity of selenium. Our earlier work indicated that distinct cell death pathways are likely involved in apoptosis induced by the CH3SeH and the hydrogen selenide pools of selenium metabolites. To explore the role of caspases in cancer cell apoptosis induced by selenium, we examined the involvement of these molecules in the death of the DU-145 human prostate carcinoma cells induced by methylseleninic acid (MSeA), a novel penultimate precursor of the putative critical anticancer metabolite CH3SeH. Sodium selenite, a representative of the genotoxic selenium pool, was used as a reference for comparison. The results show that MSeA-induced apoptosis was accompanied by the activation of multiple caspases (caspase-3, -7, -8, and -9), mitochondrial release of cytochrome c (CC), poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. In contrast, selenite-induced apoptotic DNA fragmentation was observed in the absence of these changes, but was associated with the phosphorylation of c-Jun-NH2-terminal kinase 1/2 and p38 mitogen-activated protein kinase/stress-activated protein kinase 2. A general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone, blocked MSeA-induced cleavage of procaspases and PARP, CC release, and DNA nucleosomal fragmentation, but did not prevent cell detachment. Furthermore, PARP cleavage and caspase activation were confined exclusively to detached cells, indicating that MSeA induction of cell detachment was a prerequisite for caspase activation and apoptosis execution. This process therefore resembled "anoikis," a special mode of apoptosis induction in which adherent cells lose contact with the extracellular matrix. Additional experiments with irreversible caspase inhibitors show that MSeA-induced anoikis involved caspase-3- and -7-mediated PARP cleavage that was initiated by caspase-8 and probably amplified through CC-caspase-9 activation and a feedback activation loop from caspase-3. Taken together, the data support a methyl selenium-specific induction of DU-145 cell apoptosis that involves cell detachment as a prerequisite (anoikis) and is executed principally through caspase-8 activation and its cross-talk with multiple caspases.
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PMID:Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells. 1130 88

For investigation of the killing and proapoptotic effects of sodium salicylate (Na-Sal) on HL-60 cells, the cytotoxic activity of Na-Sal was measured by means of MTT assay. Apoptosis was identified and analyzed with the help of transmission electron microscopy, annexin V staining, and DNA gel electrophoresis, and the association of caspase-8 activation with apoptosis was determined with the specific protease inhibitor IETD-fmk. After exposure of HL-60 cells to increasing concentrations of Na-Sal (0.5, 1, 3, 5, and 7 mmol/L) for 24 hours, the mean cell viability gradually dropped to 92%, 83%, 68%, 50%, and 42%. With treatment of target cells with 5-mmol/L (IC50) Na-Sal for 6, 12, 24, or 36 hours, the mean cell survival tapered to 91%, 81%, 48% (P <.05 versus control), and 14% (P <.05 versus control). Again incubated with 5-mmol/L Na-Sal for 12 or 24 hours, HL-60 cells displayed clear early or late signs of apoptosis, including (1) notable enhancement of phosphatidylserine externalization, (2) cell shrinkage, membrane blebbing, and eventual disintegration into numerous apoptotic bodies, and (3) formation of ladder DNA. The viability of HL-60 cells increased significantly during 24 or 36 hours of coculture with 100-micromol/L IETD-fmk in combination with 5-mmol/L Na-Sal compared with the viability when 5-mmol/L Na-Sal was used alone (P < .05). Moreover, the target cells showed a considerable decrease in phosphatidylserine exposure and DNA fragmentation after coincubation for 12 or 24 hours performed as described above. The findings presented herein strongly suggest that Na-Sal can exert potent killing and proapoptotic activity against HL-60 cells, and this effect appears to depend on caspase-8 activation.
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PMID:Sodium salicylate-triggered apoptosis in HL-60 cells depends on caspase-8 activation. 1204 73

L-ascorbic acid (vitamin C) has been reported to play a role in the treatment and prevention of cancer. However, its specific mechanistic pathways remain obscure. This study was carried out to identify the sodium ascorbate-induced apoptotic pathway in B16F10 murine melanoma cells. Sodium ascorbate was found to induce the apoptosis of B16F10 murine melanoma in a time- and dose-dependent manner, and this was prevented by pretreatment with N-acetyl- L-cysteine (NAC), a well-known antioxidant. In fact, sodium ascorbate-treated B16F10 melanoma cells showed increased intracellular reactive oxygen species generation (ROS) levels. These results indicate that sodium ascorbate induced apoptosis in B16F10 murine melanoma cells by acting as a prooxidant. We examined the involvement of caspase-8 using a specific caspase-8 inhibitor (z-IETD-fmk) on the sodium ascorbate-induced apoptotic pathway. Cell death was found not to be inhibited by z-IETD-fmk treatment, indicating that sodium ascorbate-induced apoptosis is not mediated by caspase-8. In addition, we detected a reduction in the mitochondrial membrane potential during apoptosis and confirmed cytochrome-c release from mitochondria by immunoblotting. Taken together, it appears that the induction of a prooxidant state by sodium ascorbate and a subsequent reduction in mitochondrial membrane potential are involved in the apoptotic pathway of B16F10 murine melanoma cells, and that this occurs in a caspase-8-independent manner.
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PMID:L-ascorbic acid (vitamin C) induces the apoptosis of B16 murine melanoma cells via a caspase-8-independent pathway. 1282 7

Interactions between histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand, were examined in human leukemia cells (e.g., U937, Jurkat, and HL-60). Simultaneous exposure of cells to 100-ng/ml TRAIL with either 1-mM sodium butyrate or 2- micro M suberoylanilide hydroxamic acid resulted in a striking increase in leukemic cell mitochondrial damage, caspase activation, and apoptosis. Lethal effects were significantly diminished in U937 cells ectopically expressing dominant-negative caspase-8, dominant-negative Fas-associated death domain, CrmA (receptor pathway), or Bcl-2 or Bcl-X(L) (mitochondrial pathway). Analysis of mitochondrial events in U937 cells exposed to TRAIL/HDAC inhibitors revealed enhanced Bid activation and Bax translocation, loss of mitochondrial membrane potential, and cytoplasmic release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor. No changes were observed in expression of FLICE-like inhibitory protein, TRAIL receptors, or reactive oxygen species generation. TRAIL/HDAC inhibitor-induced apoptosis triggered caspase-dependent cleavage of p21(WAF1/CIP1); moreover, enforced expression of a nuclear localization signal deletant form of p21(WAF1/CIP1) significantly diminished lethality. Lastly, p27(KIP1), pRb, X-linked inhibitor of apoptosis, and Bcl-2 displayed extensive proteolysis. These findings indicate that coadministration of TRAIL with HDAC inhibitors synergistically induces apoptosis in human myeloid leukemia cells and provide further evidence that simultaneous activation of the extrinsic and intrinsic pathways in such cells leads to a dramatic increase in mitochondrial injury and activation of the caspase cascade.
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PMID:Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. 1470 68

Death receptor 5 (DR5) is a receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL is a promising candidate for cancer therapeutics due to its ability to induce apoptosis selectively in cancer cells. Here, we report that histone deacetylase inhibitors (HDACIs) such as trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid (SAHA) upregulated DR5 expression in various human malignant tumor cells. An RNase protection assay demonstrated that HDACIs induced DR5 mRNA markedly but not that of other death receptor family members in Jurkat cells. HDACIs increased DR5 mRNA and protein in a dose- and time-dependent manner. We also show TSA increased DR5 promoter activity using a luciferase promoter assay. Furthermore, we demonstrated that HDACIs strongly sensitized exogenous soluble recombinant human TRAIL-induced apoptosis synergistically in Jurkat and HL-60 cells that were tolerant to TRAIL alone. The combined use of HDACIs and TRAIL in suboptimal concentrations induced Bid cleavage and activation of caspase-8, -10, -3, and -9. Human recombinant DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 and -10 inhibitors efficiently reduced apoptosis induced by cotreatment with HDACIs and TRAIL. Furthermore, TSA did not significantly induce DR5 protein and HDACIs did not enhance TRAIL-induced apoptosis in normal human peripheral blood mononuclear cells. These results suggest that this combined treatment with HDACIs and TRAIL is a promising strategy for new cancer therapeutics.
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PMID:Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. 1520 60

Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor alpha, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte-macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-kappaB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-kappaB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.
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PMID:Switching leukemia cell phenotype between life and death. 1532 18

Although arsenic and ultraviolet light B (UVB) are both causes for skin cancers, lesions of arsenic-induced Bowen's disease are often confined to sun-protected skin. UVB may play a modulatory role in skin carcinogenesis by arsenic. The purpose of this study was to evaluate the effects and interactions of arsenic and UVB on cell cycle progression and apoptosis. Cultured human keratinocytes were treated with sodium arsenite (1 microM) and/or UVB (50 mJ/cm(2)) irradiation in different combinations: (i) arsenic alone, (ii) UVB alone, (iii) arsenic followed by UVB (As-UVB), and (iv) UVB followed by arsenic (UVB-As) treatments. Cell cycle analysis and BrdU pulsing revealed S phase arrest in all treatment groups and growth arrest in As-UVB and UVB-As groups. The terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling assay showed a higher apoptosis rate in the UVB-As group as compared to that of the As-UVB and UVB groups. UVB irradiation significantly decreased Bcl-2 expression. In either the As-UVB or the UVB-As group, the expression of Bcl-2 was further suppressed as compared to the UVB group. The caspase-3, -8, and -9 relative activities were all increased in the UVB group; however, arsenic significantly enhanced caspase-8 and -3 relative activities in UVB-irradiated keratinocytes (the UVB-As group). Pretreatment with the caspase inhibitor(s) rescued the keratinocytes viability to different degrees with the least in the UVB-As group. Our findings revealed that arsenic enhances UVB-induced keratinocyte apoptosis via suppression of Bcl-2 expression and stimulation of caspase-8 activity. Combined UVB and arsenic treatment resulted in the antiproliferative and proapoptotic effects in keratinocytes. Our results provide the explanation for the rare occurrences of arsenical cancers in the sun-exposed skin and the potential therapeutic role of UVB in arsenic-induced Bowen's disease.
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PMID:Effects and interactions of low doses of arsenic and UVB on keratinocyte apoptosis. 1537 53

Inorganic arsenic is an environmental toxin and a human carcinogen. Being a co-mutagen, arsenic enhances carcinogenesis of ultraviolet irradiation on the mouse skin. Apoptosis, a well-regulated cell death process, is essential for cell development and tissue homeostasis. Dysregulation of apoptosis will lead to various kinds of pathological conditions, such as cancers. The purpose of this study is to investigate the apoptotic effect induced by the interactions of arsenic and UVB on cultured human keratinocytes. Cultured keratinocytes were treated with sodium arsenite (1 microM) and/or UVB 50 mJ/cm2 irradiation in different combinations, including arsenic alone (As group), UVB alone (UVB group), arsenic followed by UVB (As/UVB group), and UVB followed by As (UVB/As group) treatments. Our results revealed that a low concentration of sodium arsenite did not induce keratinocytes apoptosis. The UVB group showed obvious elevation of caspase-8, -9, and -3 activities in addition to strong induction of apoptosis as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling (TUNEL) assay. Similar pro-apoptotic effects were observed in the UVB/As group. In contrast, only subtle changes of cell morphology and survival rate were noticed in the As/UVB group. In addition, the results of Western blot and activity assay of caspase-8, -9, and -3 revealed that neither the receptor nor the mitochondrial apoptotic signaling pathway was activated in the As/UVB group. Therefore, we conclude that the pretreatment of keratinocytes with sodium arsenite decreased the pro-apoptotic effects induced by UVB. This finding corroborated with the animal model studying the effects of arsenic and UVB on carcinogenesis. The molecular mechanisms by which arsenic decreased UVB-induced apoptosis remain to be elucidated.
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PMID:Effects of arsenic and UVB on normal human cultured keratinocytes: impact on apoptosis and implication on photocarcinogenesis. 1572 Jan 17


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