EC:3.4.22.61 - FACTA Search

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)

Tocotrienols, a subclass in the vitamin E family of compounds, have been shown to induce apoptosis by activating caspase-8 and caspase-3 in neoplastic mammary epithelial cells. Since caspase-8 activation is associated with death receptor apoptotic signaling, studies were conducted to determine the exact death receptor/ligand involved in tocotrienol-induced apoptosis. Highly malignant +SA mouse mammary epithelial cells were grown in culture and maintained in serum-free media. Treatment with 20 microM gamma-tocotrienol decreased+SA cell viability by inducing apoptosis, as determined by positive terminal dUTP nick end labeling (TUNEL) immunocytochemical staining. Western blot analysis showed that gamma-tocotrienol treatment increased the levels of cleaved (active) caspase-8 and caspase-3. Combined treatment with caspase inhibitors completely blocked tocotrienol-induced apoptosis. Additional studies showed that treatment with 100 ng/ml tumor necrosis factor-alpha (TNF-alpha), 100 ng/ml FasL, 100 ng/ml TNF-related apoptosis-inducing ligand (TRAIL), or 1 microg/ml apoptosis-inducing Fas antibody failed to induce death in +SA cells, indicating that this mammary tumor cell line is resistant to death receptor-induced apoptosis. Furthermore, treatment with 20 microM gamma-tocotrienol had no effect on total, membrane, or cytosolic levels of Fas, Fas ligand (FasL), or Fas-associated via death domain (FADD) and did not induce translocation of Fas, FasL, or FADD from the cytosolic to the membrane fraction, providing additional evidence that tocotrienol-induced caspase-8 activation is not associated with death receptor apoptotic signaling. Other studies showed that treatment with 20 microM gamma-tocotrienol induced a large decrease in the relative intracellular levels of phospho-phosphatidylinositol 3-kinase (PI3K)-dependent kinase 1 (phospho-PDK-1 active), phospho-Akt (active), and phospho-glycogen synthase kinase3, as well as decreasing intracellular levels of FLICE-inhibitory protein (FLIP), an antiapoptotic protein that inhibits caspase-8 activation, in these cells. Since stimulation of the PI3K/PDK/Akt mitogenic pathway is associated with increased FLIP expression, enhanced cellular proliferation, and survival, these results indicate that tocotrienol-induced caspase-8 activation and apoptosis in malignant +SA mammary epithelial cells is associated with a suppression in PI3K/PDK-1/Akt mitogenic signaling and subsequent reduction in intracellular FLIP levels.
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PMID:Tocotrienol-induced caspase-8 activation is unrelated to death receptor apoptotic signaling in neoplastic mammary epithelial cells. 1533 28

More than 99% of follicles undergo a degenerative process known as "atresia", in mammalian ovaries, and only a few follicles ovulate during ovarian follicular development. We have investigated the molecular mechanism of selective follicular atresia in mammalian ovaries, and have reported that follicular selection dominantly depends on granulosa cell apoptosis. However, we have little knowledge of the molecular mechanisms that control apoptotic cell death in granulosa cells during follicle selection. To date, at least five cell death ligand-receptor systems [tumor necrosis factor (TNF)alpha and receptors, Fas (also called APO-1/CD95) ligand and receptors, TNF-related apoptosis-inducing ligand (TRAIL; also called APO-2) and receptors, APO-3 ligand and receptors, and PFG-5 ligand and receptors] have been reported in granulosa cells of porcine ovaries. Some cell death ligand-receptor systems have "decoy" receptors, which act as inhibitors of cell death ligand-induced apoptosis in granulosa cells. Moreover, we showed that the porcine granulosa cell is a type II apoptotic cell, which has the mitochondrion-dependent apoptosis-signaling pathway. Briefly, the cell death receptor-mediated apoptosis signaling pathway in granulosa cells has been suggested to be as follows. (1) A cell death ligand binds to the extracellular domain of a cell death receptor, which contains an intracellular death domain (DD). (2) The intracellular DD of the cell death receptor interacts with the DD of the adaptor protein (Fas-associated death domain: FADD) through a homophilic DD interaction. (3) FADD activates an initiator caspase (procaspase-8; also called FLICE), which is a bipartite molecule, containing an N-terminal death effector domain (DED) and a C-terminal DD. (4) Procaspase-8 begins auto-proteolytic cleavage and activation. (5) The auto-activated caspase-8 cleaves Bid protein. (6) The truncated Bid releases cytochrome c from mitochondrion. (7) Cytochrome c and ATP-dependent oligimerization of apoptotic protease-activating factor-1 (Apaf-1) allows recruitment of procaspase-9 into the apoptosome complex. Activation of procaspase-9 is mediated by means of a conformational change. (8) The activated caspase-9 cleaves downstream effector caspases (caspase-3). (9) Finally, apoptosis is induced. Recently, we found two intracellular inhibitor proteins [cellular FLICE-like inhibitory protein short form (cFLIPS) and long form (cFLIPL)], which were strongly expressed in granulosa cells, and they may act as anti-apoptotic/survival factors. Further in vivo and in vitro studies will elucidate the largely unknown molecular mechanisms, e. g. which cell death ligand-receptor system is the dominant factor controlling the granulosa cell apoptosis of selective follicular atresia in mammalian ovaries. If we could elucidate the molecular mechanism of granulosa cell apoptosis (follicular selection), we could accurately diagnose the healthy ovulating follicles and precisely evaluate the oocyte quality. We hope that the mechanism will be clarified and lead to an integrated understanding of the regulation mechanism.
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PMID:Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia. 1551 56

Identification of mechanisms of modulation of the TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is important for its potential use in anticancer therapy. Ethanol can induce cell death in vitro and in vivo by different signalling pathways. Its effect in combination with death ligands is unknown. We investigated how ethanol modulates the effects of TRAIL in colon cancer cells. After combined TRAIL and ethanol treatment, a potentiation of caspase-8, -9, -3 activation, a proapoptotic Bid protein cleavage, a decrease of mitochondrial membrane potential, a complete poly(ADP)ribose polymerase cleavage, and disappearance of antiapoptotic Mcl-1 protein were demonstrated. Ethanol acts as a potent agent sensitizing colon cancer cells to TRAIL-induced apoptosis.
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PMID:Ethanol acts as a potent agent sensitizing colon cancer cells to the TRAIL-induced apoptosis. 1552 5

The plant-produced compound, resveratrol (3,5,4'-trihydroxy-trans-stilbene, 3,4,5-THS), induces apoptosis in various human leukemia cell types in vitro, and thus appears to be a promising anti-leukemia agent. In this study, we observed that treatment of resveratrol-resistant Jurkat cells with the resveratrol analogue, 3,4,5-trihydroxy-trans-stilbene (3,4,5-THS), rapidly induced extensive apoptosis, indicating that the apoptotic activity of the analogue differed from that of the parental compound resveratrol. Indeed, we found that treatment of Jurkat cells with 3,4,5-THS, unlike treatment with resveratrol, induced activation of caspase-8 and apoptosis by a Fas-associated death domain (FADD) protein-dependent mechanism without involving the known death ligands CD95 ligand (CD95L), tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL). Therefore, 3,4,5-THS induced activation of a FADD-dependent apoptotic mechanism that was unresponsive to the parental compound resveratrol. Therefore, the ability of 3,4,5-THS, but not resveratrol, to induce apoptosis demonstrates a structure-associated apoptotic activity of the resveratrol analogue.
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PMID:FADD-dependent apoptosis induction in Jurkat leukemia T-cells by the resveratrol analogue, 3,4,5-trihydroxy-trans-stilbene. 1562 77

Mouse TOSO, the homologue of human TOSO gene, was cloned and characterized in the present study. Using immunofluorescence confocal microscopy we localized TOSO to the cytoplasmic membrane of expressing cells. Using stably transfected mouse TOSO (mTOSO)-expressing Jurkat cells, we show that TOSO protects cells from Fas/Fas ligand- and tumor necrosis factor-induced apoptosis but not from TNF-related apoptosis-inducing ligand-induced apoptosis. The Fas-induced activation of caspase-8 was significantly inhibited by the expression of mTOSO. Using deletion mutants and glutathione S-transferase pull-down approaches, we have shown that mTOSO regulates apoptosis by directly binding to Fas-associated death domain through its C-terminal domain, suggesting the disruption of death-inducing signaling complex formation as mechanism of action. Furthermore, we have expressed mTOSO in transgenic mice and show that mTOSO overexpressing primary T lymphocytes are resistant to Fas/Fas ligand-induced apoptosis.
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PMID:The mouse cell surface protein TOSO regulates Fas/Fas ligand-induced apoptosis through its binding to Fas-associated death domain. 1563 12

Resistance to apoptosis has been implicated in the poor response of cancer cells to various anti-tumor agents. Caspase-8 is a family member of executioner caspases associated with tumor necrosis factor (TNF) family death receptors-mediated apoptotic signaling cascade. In this study, to specify caspase-8-mediated apoptotic activity, we examined the anti-tumor effect of adenoviral vector expressing caspase-8 (Adv-caspase-8) in combination with TNF-related apoptosis-inducing ligand (TRAIL) which induces specifically caspase-8 activation. First, we demonstrated that expression procaspase-8 is related to apoptosis sensitivity to TRAIL in pancreatic and colonic cancer cells. In human pancreatic cancer cell line Panc1 which demonstrates low expression of procaspase-8, Adv-caspase-8 transfection strongly augmented TRAIL-induced apoptosis. Adv-caspase-8 similarly enhanced the susceptibility of human colonic cancer cell line Colo320DM to TRAIL. These results suggest that Adv-caspase-8 may be a good combination partner of TRAIL and enables TRAIL to be a more potent anticancer agent in a wide range of adenocarcinoma cells which demonstrate low expression of caspase-8.
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PMID:Adenovirus-mediated gene transfer of caspase-8 sensitizes human adenocarcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand. 1564 41

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

Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli, as well as being elevated in many human cancers examined. We have demonstrated that CK2 is a key survival factor that protects human colon carcinoma cells from TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. We determined that inhibition of CK2 phosphorylation events by DRB (5,6-dichlorobenzimidazole) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis, in the absence of effects in normal cells. Sensitization was caspase dependent, and independent of regulation via NF-kappaB. Further, inhibition of phosphorylation by CK2 did not modify the expression level of antiapoptotic proteins. Analysis of TRAIL-induced death-inducing signaling complex (DISC) formation demonstrated enhanced formation of the DISC, enhanced cleavage of caspase-8 and cleavage of Bid in the presence of DRB, thereby facilitating the release of proapoptotic factors from the mitochondria with subsequent downregulation of the expression of XIAP and c-IAP1. Further, silencing of CK2alpha in HT29 cells following transfection of CK2alpha shRNA abrogated CK2 kinase activity while simultaneously increasing TRAIL sensitivity. These findings demonstrate that CK2 plays a critical antiapoptotic role by conferring resistance to TRAIL at the level of the DISC.
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PMID:Casein kinase II (CK2) enhances death-inducing signaling complex (DISC) activity in TRAIL-induced apoptosis in human colon carcinoma cell lines. 1568 23

Type I interferon (IFN)-induced antitumor action is due in part to apoptosis, but the molecular mechanisms underlying IFN-induced apoptosis remain largely unresolved. In the present study, we demonstrate that IFN-beta induced apoptosis and the loss of mitochondrial membrane potential (delta psi m) in the murine CH31 B lymphoma cell line, and this was accompanied by the up-regulation of CD95, but not CD95-ligand (CD95-L), tumor necrosis factor (TNF), or TNF-related apoptosis-inducing ligand (TRAIL). Pretreatment with anti-CD95-L mAb partially prevented the IFN-beta-induced loss of delta psi m, suggesting that the interaction of IFN-beta-up-regulated CD95 with CD95-L plays a crucial role in the induction of fratricide. IFN-beta induced a sustained activation of c-Jun NH2-terminal kinase 1 (JNK1), but not extracellular signal-regulated kinases (ERKs). The IFN-beta-induced apoptosis and loss of delta psi m were substantially compromised in cells overexpressing a dominant-negative form of JNK1 (dnJNK1), and it was slightly enhanced in cells carrying a constitutively active JNK construct, MKK7-JNK1 fusion protein. The IFN-beta-induced up-regulation of CD95 together with caspase-8 activation was also abrogated in the dnJNK1 cells while it was further enhanced in the MKK7-JNK1 cells. The levels of cellular FLIP (c-FLIP), competitively interacting with caspase-8, were down-regulated by stimulation with IFN-beta but were reversed by the proteasome inhibitor lactacystin. Collectively, the IFN-beta-induced sustained activation of JNK mediates apoptosis, at least in part, through up-regulation of CD95 protein in combination with down-regulation of c-FLIP protein.
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PMID:Interferon-beta-induced activation of c-Jun NH2-terminal kinase mediates apoptosis through up-regulation of CD95 in CH31 B lymphoma cells. 1574 96

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily known to induce apoptosis in a variety of cancers. The purpose of our study was to examine the effects of TRAIL in combination with cisplatin against esophageal squamous cell carcinoma (ESCC) cell lines in vitro and in vivo, and to elucidate underlying molecular mechanisms. Expression profiles of TRAIL receptors were investigated in 19 ESCC (KYSE) cell lines using RT-PCR. Crystal violet staining assays were performed to reveal the sensitivity against TRAIL. Flow cytometric analyses of apoptosis induction and TRAIL receptor expression were performed. Furthermore, Western blot was used to clarify the apoptosis pathway involved, and a nude-mouse xenograft model was used to show effects in vivo. Results show that death receptors (DR) 4 and 5 were expressed in 100% of the cell lines, and 79% (15/19) expressed 4 TRAIL receptors. There was only 1 cell line without decoy receptor expression. Eighteen cell lines were resistant to TRAIL, but in some, the combination treatment with cisplatin could overcome this resistance. They underwent apoptosis via activation of caspase-8 and -3, and cisplatin-dependent upregulation of DR4 and 5 was detected. Furthermore, pretreatment with cisplatin followed by TRAIL resulted in significant tumoricidal effects. Finally, systemic administration of TRAIL with cisplatin synergistically suppressed tumor growth of ESCC xenografts in nude mice. These results provide a significance of cisplatin-induced upregulation of death receptors as apoptosis-inducing machinery, and it was suggested that sequential administration of cisplatin and TRAIL might be a feasible chemotherapeutic regimen against ESCC.
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PMID:Cisplatin-dependent upregulation of death receptors 4 and 5 augments induction of apoptosis by TNF-related apoptosis-inducing ligand against esophageal squamous cell carcinoma. 1600 25

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