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)

Recently, we identified Insulinoma-Glucagonoma clone 20 (IG20) that can render cells more susceptible to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. In addition, it can slow cell proliferation, and enhance drug- and radiation-induced cell death. TNF-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in some cancer cells and render others susceptible to cotreatment with drugs and irradiation, with little or no effect on most normal cells. In this study, we investigated the potential of IG20 to enhance TRAIL-induced apoptosis and found that it can render cells more susceptible to TRAIL treatment through enhanced activation of caspases. Further, we showed that this effect can be suppressed by caspase inhibitors, p35 and CrmA, and a dominant-negative Fas-associated death domain-containing protein (DN-FADD). Results from colocalization and immunoprecipitation studies showed that IG20 can interact with TRAIL death receptors (DR), DR4 and DR5 and increase recruitment of FADD and caspase-8 into the TRAIL death-inducing signaling complex (DISC). These results indicate that IG20 is a novel protein that can enhance TRAIL-induced apoptosis by facilitating DISC formation.
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PMID:IG20 (MADD splice variant-5), a proapoptotic protein, interacts with DR4/DR5 and enhances TRAIL-induced apoptosis by increasing recruitment of FADD and caspase-8 to the DISC. 1520 70

Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAIL-induced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.
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PMID:FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells. 1533 61

Interactions between the cyclin-dependent kinase inhibitor flavopiridol (FP) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L), were examined in human leukemia cells (U937 and Jurkat). Coexposure of cells to marginally toxic concentrations of TRAIL and FP (24 h) synergistically increased mitochondrial injury (eg, cytochrome c, AIF, Smac/DIABLO release), cytoplasmic depletion of Bax, activation of Bid as well as caspase-8 and -3, PARP cleavage, and apoptosis. Coadministration of TRAIL markedly increased FP-induced apoptosis in leukemic cells ectopically expressing Bcl-2, Bcl-x(L), or a phosphorylation loop-deleted form of Bcl-2 (DeltaBcl-2), whereas lethality was substantially attenuated in cells ectopically expressing CrmA, dominant-negative-FADD, or dominant-negative-caspase-8. TRAIL/FP induced no discernible changes in FLIP, DR4, DR5, Mcl-1, or survivin expression, modest declines in levels of DcR2 and c-IAP, but resulted in the marked transcriptional downregulation of XIAP. Moreover, cells stably expressing an XIAP-antisense construct exhibited a pronounced increase in TRAIL sensitivity comparable to degrees of apoptosis achieved with TRAIL/FP. Conversely, enforced XIAP expression significantly attenuated caspase activation and TRAIL/FP lethality. Together, these findings suggest that simultaneous activation of the intrinsic and extrinsic apoptotic pathways by TRAIL and FP synergistically induces apoptosis in human leukemia cells through a mechanism that involves FP-mediated XIAP downregulation.
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PMID:Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. 1538 34

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via the death receptors DR4 and DR5 in transformed cells in vitro and exhibits potent antitumor activity in vivo with minor side effects. Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli and is aberrantly elevated in a variety of human cancers. Rhabdomyosarcoma tumors are the most common soft-tissue sarcoma in childhood. In this investigation, we demonstrate that CK2 is a key survival factor that protects tumor cells from TRAIL-induced apoptosis. We have demonstrated that inhibition of CK2 phosphorylation events by 5,6-dichlorobenzimidazole (DRB) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis. CK2 inhibition also induced rapid cleavage of caspase-8, -9, and -3, as well as the caspase substrate poly(ADP-ribose) polymerase after TRAIL treatment. Overexpression of Bcl-2 protected cells from TRAIL-induced apoptosis in the presence of the CK2 inhibitor. Death signaling by TRAIL in these cells was Fas-associated death domain and caspase dependent because dominant negative Fas-associated death domain or the cowpox interleukin 1beta-converting enzyme inhibitor protein cytokine response modifier A prevented apoptosis in the presence of DRB. Analysis of death-inducing signaling complex (DISC) formation demonstrated that inhibition of CK2 by DRB increased the level of recruitment of procaspase-8 to the DISC and enhanced caspase-8-mediated cleavage of Bid, thereby increasing the release of the proapoptotic factors cytochrome c, HtrA2/Omi, Smac/DIABLO, and apoptosis inducing factor (AIF) from the mitochondria, with subsequent degradation of X-linked inhibitor of apoptosis protein (XIAP). To further interfere with CK2 function, JR1 and Rh30 cells were transfected with either short hairpin RNA targeted to CK2alpha or kinase-inactive CK2alpha (K68M) or CK2alpha' (K69M). Data show that the CK2 kinase activity was abrogated and that TRAIL sensitivity in both cell lines was increased. Silencing of CK2alpha expression with short hairpin RNA was also associated with degradation of XIAP. These findings suggest that CK2 regulates TRAIL signaling in rhabdomyosarcoma by modulating TRAIL-induced DISC formation and XIAP expression.
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PMID:Influence of casein kinase II in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human rhabdomyosarcoma cells. 1603 52

The majority of high-risk neuroblastomas lack the expression of caspase-8 due to gene silencing which suggest a mechanism for the selection of tumour cells that are refractory to multiple cytotoxic drugs including tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Inhibitors of DNA methyltransferases and IFN-gamma induce expression of caspase-8, and sensitise some neuroblastoma cells to TRAIL-mediated apoptosis. Here we demonstrate that a combination of cytostatic drugs with IFN-gamma and TRAIL synergistically induces neuroblastoma cell death, which may have implications for future therapy of children with neuroblastoma. Treatment of neuroblastoma cells with IFN-gamma induced caspase-8 expression in all cell lines investigated. In five of the neuroblastoma cell lines (SHEP-1, SK-N-AS, SK-N-FI, SH-SY-5Y and Kelly), IFN-gamma promoted TRAIL-mediated cleavage of caspase-8, initiating a caspase cascade involving caspase-7 and PARP followed by apoptosis. IFN-gamma-mediated facilitation of apoptosis was inhibited by the pan-caspase inhibitor zVAD-fmk and the caspase-8 specific inhibitor zIEDT-fmk, indicating an important role of caspase-8 in mediating sensitation by IFN-gamma in neuroblastoma cells. In three of the cell lines [SK-N-BE(2), SK-N-DZ and IMR-32] caspase-8 expression was induced by IFN-gamma, but the cells were still resistant to TRAIL-mediated apoptosis. The pattern of basal TRAIL receptor expression, decoy receptors, FLIP and FADD could not be correlated with resistance or sensitivity to TRAIL-induced apoptosis. Importantly, treatment of neuroblastoma cell lines with cytostatic drugs increased apoptosis in the TRAIL-sensitive cell lines whereas the resistant cell lines were susceptible to TRAIL-mediated apoptosis in the presence of the anticancer drugs. The mechanism of the increased susceptibility to apoptosis might results from drug-mediated up-regulation of the death receptors DR4 and DR5.
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PMID:Synergistic induction of apoptosis in neuroblastoma cells using a combination of cytostatic drugs with interferon-gamma and TRAIL. 1554 26

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, considerable numbers of cancer cells, especially some highly malignant tumors, are resistant to apoptosis induction by TRAIL, and some cancer cells that were originally sensitive to TRAIL-induced apoptosis can become resistant after repeated exposure (acquired resistance). Understanding the mechanisms underlying such resistance and developing strategies to overcome it are important for the successful use of TRAIL for cancer therapy. Resistance to TRAIL can occur at different points in the signaling pathways of TRAIL-induced apoptosis. Dysfunctions of the death receptors DR4 and DR5 due to mutations can lead to resistance. The adaptor protein Fas-associated death domain (FADD) and caspase-8 are essential for assembly of the death-inducing signaling complex, and defects in either of these molecules can lead to TRAIL resistance. Overexpression of cellular FADD-like interleukin-1beta-converting enzyme-inhibitory protein (cFLIP) correlates with TRAIL resistance in several types of cancer. Overexpression of Bcl-2 or Bcl-X(L), loss of Bax or Bak function, high expression of inhibitor of apoptosis proteins, and reduced release of second mitochondria-derived activator of caspases (Smac/Diablo) from the mitochondria to the cytosol have all been reported to result in TRAIL resistance in mitochondria-dependent type II cancer cells. Finally, activation of different subunits of mitogen-activated protein kinases or nuclear factor-kappa B can lead to development of either TRAIL resistance or apoptosis in certain types of cancer cells.
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PMID:Mechanisms of resistance to TRAIL-induced apoptosis in cancer. 1555 Sep 37

Myelodysplastic syndromes (MDSs) are characterized by peripheral blood cytopenia including anemia. We have investigated the implication of the extrinsic pathway of apoptosis in MDS-ineffective erythropoiesis by in vitro expansion of erythroid precursors from early stage (low and intermediate-1 International Prognosis Scoring System [IPSS]) MDS, advanced stage (intermediate-2 IPSS) MDS, and control bone marrow samples. We have previously shown that Fas and its ligand were overexpressed in early stage MDS erythroid cells. Here, we show that caspase-8 activity is significantly increased, whereas the expression of death receptors other than Fas, including the type 1 receptor for tumor necrosis factor alpha (TNF-alpha) and the receptors for the TNF-related apoptosis-inducing ligand (TRAIL), DR4 and DR5, was normal. We also observed that the adapter Fas-associated death domain (FADD) was overexpressed in early stage MDS erythroid cells. Transduction of early stage MDS-derived CD34+ progenitors with a FADD-encoding construct increased apoptosis of erythroid cells and dramatically reduced erythroid burst-forming unit (BFU-E) growth. Transduction of a dominant-negative (dn) mutant of FADD inhibited caspase-8 activity and cell death and rescued BFU-E growth without abrogating erythroid differentiation. These results extend the observation that Fas-dependent activation of caspase-8 accounts for apoptosis of early stage MDS erythroid cells and demonstrate for the first time that FADD is a valuable target to correct ineffective erythropoiesis in these syndromes.
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PMID:Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD. 1567 68

Ginsenoside Rh2 (Rh2), a purified ginseng saponin, has been shown to have antiproliferative effects in certain cancer cell types. However, the molecular mechanisms of Rh2 on cell growth and death have not been fully clarified. In this study, the antiproliferative effect of Rh2 in human lung adenocarcinoma A549 cells was investigated. Treatment of A549 cells with 30 mug/ml Rh2 resulted in G(1) phase arrest, followed by progression to apoptosis. This Rh2-mediated G(1) arrest was accompanied by downregulation of the protein levels and kinase activities of cyclin-D1, cyclin-E and Cdk6, and the upregulation of pRb2/p130. In addition, Rh2-induced apoptosis was confirmed by TUNEL assay and DNA fragmentation analysis. Administration of Rh2 caused an increase in the expression levels of TRAIL-RI (DR4) death receptor but did not alter the levels of other death receptors or Bcl-2 family molecules. Furthermore, the Rh2-induced apoptosis was significantly inhibited by DR4:Fc fusion protein, which inhibits TRAIL-DR4-mediated apoptosis. In addition, caspase-2, caspase-3 and caspase-8 were highly activated upon Rh2 treatment. Inhibitors of caspase-2, caspase-3 and caspase-8 markedly prevented the cell death induced by Rh2. Inhibitor of caspase-8 significantly inhibited the activation of caspase-2, caspase-3 and caspase-8. These observations indicate that multiple G(1)-related cell cycle regulatory proteins are regulated by Rh2 and contribute to Rh2-induced G(1) growth arrest. The increase in the expression level of DR4 death receptor may play a critical role in the initiation of Rh2-triggered apoptosis, and the activation of the caspase-8/caspase-3 cascade acts as the executioner of the Rh2-induced death process.
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PMID:Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. 1573 95

The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate-induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.
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PMID:Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells. 1576 47

Most tumor cells are sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis but sparing to normal cells, thus providing therapeutic potential for clinical use. Some tumor cells are resistant to TRAIL-induced cell death while the sensitivity could be recruited with the existence of some chemical agents. In this study, human prostatic cancer cell line LNCaP was found to be resistant to TRAIL-induced apoptosis while it could be restored to TRAIL sensitivity with combination treatment of low concentration of doxorubicin. TRAIL receptor-1 (DR4) and TRAIL receptor-2 (DR5) were upregulated under the treatment of doxorubicin and verified to be responsible for TRAIL-mediated signal transduction. Furthermore, caspase-8 and caspase-3 were activated and drove their autocleavage into programmed cell death. Interestingly, apoptosis-inhibitory protein c-FLIP, but not Bcl-2 and XIAP was downregulated after doxorubicin treatment. Taken together, these findings suggested that the pathway of cell apoptosis induced by TRAIL was intact but under negative control. Subtoxic concentration of doxorubicin effectively boosted TRAIL sensitivity via depletion of antiapoptotic protein. These findings support the new strategies for killing tumors with TRAIL and chemical agents.
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PMID:Subtoxic concentration of doxorubicin enhances TRAIL-induced apoptosis in human prostate cancer cell line LNCaP. 1589 17


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