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)

Stimulation of cell surface Fas (CD95) results in recruitment of cytoplasmic proteins and activation of caspase-8, which in turn activates downstream effector caspases leading to programmed cell death. Nitric oxide (NO) plays a key role in the regulation of apoptosis, but its role in Fas-induced cell death and the underlying mechanism are largely unknown. Here we show that stimulation of the Fas receptor by its ligand (FasL) results in rapid generation of NO and concomitant decrease in cellular FLICE inhibitory protein (FLIP) expression without significant effect on Fas and Fas-associated death domain (FADD) adapter protein levels. FLIP down-regulation as well as caspase-8 activation and apoptosis induced by FasL were all inhibited by the NO-liberating agent sodium nitroprusside and dipropylenetriamine NONOate, whereas the NO synthase inhibitor aminoguanidine and NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had opposite effects, indicating an anti-apoptotic role of NO in the Fas signaling process. FasL-induced down-regulation of FLIP is mediated by a ubiquitin-proteasome pathway that is negatively regulated by NO. S-nitrosylation of FLIP is an important mechanism rendering FLIP resistant to ubiquitination and proteasomal degradation by FasL. Deletion analysis shows that the caspase-like domain of FLIP is a key target for S-nitrosylation by NO, and mutations of its cysteine 254 and cysteine 259 residues completely inhibit S-nitrosylation, leading to increased ubiquitination and proteasomal degradation of FLIP. These findings indicate a novel pathway for NO regulation of FLIP that provides a key mechanism for apoptosis regulation and a potential new target for intervention in death receptor-associated diseases.
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PMID:Nitric oxide negatively regulates Fas CD95-induced apoptosis through inhibition of ubiquitin-proteasome-mediated degradation of FLICE inhibitory protein. 1624 40

Exogenous overexpression of hRFI, originally isolated in our laboratory, inhibits not only death receptor-mediated apoptosis but also the mitochondrial apoptosis induced by several chemotherapeutic agents including 5-fluorouracil (5-FU). Recently, it has become clear that hRFI targets and degradates caspase-8 and -10 in death receptor-mediated apoptosis by E3 ubiquitin activity in a ring finger domain homologous to that of X-chromosome-linked inhibitor of apoptosis protein (XIAP). However, the cellular mechanism of the inhibition of mitochondrial apoptosis by hRFI has not been fully elucidated. We prepared HCT116 overexpressing hRFI (HCT116/hRFI) cells and comprehensively analyzed the expression changes of 51 apoptosis-related genes with or without 5-FU treatment between HCT116/hRFI and mock cells using microfluidic low-density arrays. As a result, we identified four genes (Bcl-2, Bcl-XL, cIAP2, and CFLAR) whose expression was four or more times higher in HCT116/ hRFI cells than in HCT116/LacZ cells, and found that Bcl-2 and the ratio of Bcl-2/Bax or Bcl-2/Bak were upregulated when HCT116/hRFI cells were treated with 5-FU. Furthermore, we also validated the up-regulation of Bcl-2 and Bcl-XL in HCT116/hRFI cells treated with 5-FU by Western blot analysis. Such evidence suggests that the modulation of Bcl-2 family proteins seen in 5-FU treatment plays an important role in the anti-apoptotic function of HCT116/hRFI cells.
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PMID:hRFI overexpressed in HCT116 cells modulates Bcl-2 family proteins when treated with 5-fluorouracil. 1659

In this study, we have investigated the underlying molecular mechanism for the potent proapoptotic effect of luteolin on human hepatoma cells both in vitro and in vivo, focusing on the signal transducer and activator of transcription 3 (STAT3)/Fas signaling. A clear apoptosis was found in the luteolin-treated HLF hepatoma cells in a time- and dosage-dependent manner. In concert with the caspase-8 activation by luteolin, an enhanced expression in functional Fas/CD95 was identified. Consistent with the increased Fas/CD95 expression, a drastic decrease in the Tyr(705) phosphorylation of STAT3, a known negative regulator of Fas/CD95 transcription, was found within 20 minutes in the luteolin-treated cells, leading to down-regulation in the target gene products of STAT3, such as cyclin D1, survivin, Bcl-xL, and vascular endothelial growth factor. Of interest, the rapid down-regulation in STAT3 was consistent with an accelerated ubiquitin-dependent degradation in the Tyr(705)-phosphorylated STAT3, but not the Ser(727)-phosphorylated one, another regulator of STAT3 activity. The expression level of Ser(727)-phosphorylated STAT3 was gradually decreased by the luteolin treatment, followed by a fast and clear down-regulation in the active forms of CDK5, which can phosphorylate STAT3 at Ser(727). An overexpression in STAT3 led to resistance to luteolin, suggesting that STAT3 was a critical target of luteolin. In nude mice with xenografted tumors using HAK-1B hepatoma cells, luteolin significantly inhibited the growth of the tumors in a dosage-dependent manner. These data suggested that luteolin targeted STAT3 through dual pathways-the ubiquitin-dependent degradation in Tyr(705)-phosphorylated STAT3 and the gradual down-regulation in Ser(727)-phosphorylated STAT3 through inactivation of CDK5, thereby triggering apoptosis via up-regulation in Fas/CD95.
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PMID:Luteolin promotes degradation in signal transducer and activator of transcription 3 in human hepatoma cells: an implication for the antitumor potential of flavonoids. 1665 38

The cyclin-dependent kinase inhibitor flavopiridol is undergoing clinical trials as an antitumor drug. We show here that pretreatment of different human breast cancer cell lines with flavopiridol facilitates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. In breast tumor cells, apoptosis induction by TRAIL is blocked at the level of apical caspase-8 activation. Flavopiridol treatment enhances TRAIL-induced formation of death-inducing signaling complex and early processing of procaspase-8. Subsequently, a TRAIL-induced, mitochondria-operated pathway of apoptosis is activated in cells treated with flavopiridol. Down-regulation of cellular FLICE-inhibitory proteins (c-FLIP; c-FLIP(L) and c-FLIP(S)) is observed on flavopiridol treatment. c-FLIP loss and apoptosis sensitization by flavopiridol are both prevented in cells treated with an inhibitor of the ubiquitin-proteasome system. Furthermore, targeting c-FLIP directly with small interfering RNA oligonucleotides also sensitizes various human breast tumor cell lines to TRAIL-induced apoptosis. Our results indicate that flavopiridol sensitizes breast cancer cells to TRAIL-induced apoptosis by facilitating early events in the apoptotic pathway, and this combination treatment could be regarded as a potential therapeutic tool against breast tumors.
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PMID:Flavopiridol induces cellular FLICE-inhibitory protein degradation by the proteasome and promotes TRAIL-induced early signaling and apoptosis in breast tumor cells. 1695 Dec 3

Total parenteral nutrition (TPN) induces a high rate of liver disease in infants, yet the pathogenesis remains elusive. We used neonatal piglets as an animal model to assess early events leading to TPN-mediated liver injury. Newborn piglets (n = 7) were nourished for 7 d on TPN or enteral nutrition (EN) and the liver tissue and isolated hepatocytes were subjected to morphologic and molecular analysis. Histological analysis revealed prominent steatosis (grade > 2) in 6 of 7 TPN pigs, whereas minimal steatosis (grade < or = 1) was observed in only 2 EN pigs. Abundant cytosolic cytochrome C and DNA fragmentation were observed in hepatocytes from TPN compared with EN piglets. Markers of mitochondrial and Fas-mediated apoptosis were altered in TPN liver tissue, as indicated by a lower ATP concentration (P < 0.05), accumulation of ubiquitin, 9.9-fold activation of caspase-3 activity (P < 0.01), and increased cleavage of poly-(ADP-ribose) polymerase, caspase-8, -9, and -7 when compared with EN livers. Bcl-2 and proliferating cell nuclear antigen expression was downregulated, whereas Fas and Bax were upregulated in TPN livers. However, levels of caspase-12 and Bip/GRP78, both markers of endoplasmic reticulum-mediated apoptosis, did not differ between the groups. Short-term TPN induces steatosis and oxidative stress, which results in apoptosis mediated by the mitochondrial and Fas pathways. Thus, TPN-induced steatosis in newborn piglets may serve as a novel animal model to assess the pathogenesis of fatty liver and apoptosis-mediated liver injury in infants.
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PMID:Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets. 1698 24

Geldanamycin, a heat-shock protein 90 (Hsp90)-binding agent, modulates various cellular activities. The present study found that, although geldanamycin by itself had no effect on thymocyte viability, it induced apoptosis in thymocytes with a reduction of the mitochondrial transmembrane potential (DeltaPsim) in the presence of 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C (PKC). This apoptosis depended on transcription and translation, and on activation of caspase-8 and -3. Geldanamycin treatment in the presence of TPA also enhanced destabilization of Lck. This destabilization was independent of transcription and translation. It was inhibited, however, by conventional PKC inhibitors, preventing apoptosis. Proteasome inhibitor affected neither the degradation of Lck nor DNA fragmentation, although they inhibited reduction of DeltaPsim. These results suggest that the ubiquitin-proteasome system is not involved in Lck destabilization, and that DeltaPsim reduction is not directly related to the progression of apoptosis. Furthermore, inhibition of Lck in the presence of TPA induced apoptosis in thymocytes. Our findings suggest that Hsp90 modulates thymocyte apoptosis in concert with PKC through the destabilization of Lck and in a caspase-8- and -3-dependent manner.
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PMID:Geldanamycin, a heat-shock protein 90-binding agent, induces thymocyte apoptosis through destabilization of Lck in presence of 12-O-tetradecanoylphorbol 13-acetate. 1737 55

Targeting the ubiquitin-proteasome pathway has emerged as a potent anticancer strategy. Bortezomib, a specific proteasome inhibitor, has been approved for the treatment of relapsed or refractory multiple myeloma. Multiple myeloma cell survival is highly dependent on Mcl-1 antiapoptotic molecules. In a recent study, proteasome inhibitors induced Mcl-1 accumulation that slowed down their proapoptotic effects. Consequently, we investigated the role of Bcl-2 family members in bortezomib-induced apoptosis. We found that bortezomib induced apoptosis in five of seven human myeloma cell lines (HMCL). Bortezomib-induced apoptosis was associated with Mcl-1 cleavage regardless of Mcl-1L accumulation. Furthermore, RNA interference mediated Mcl-1 decrease and sensitized RPMI-8226 HMCL to bortezomib, highlighting the contribution of Mcl-1 in bortezomib-induced apoptosis. Interestingly, an important induction of Noxa was found in all sensitive HMCL both at protein and mRNA level. Concomitant to Mcl-1 cleavage and Noxa induction, we also found caspase-3, caspase-8, and caspase-9 activation. Under bortezomib treatment, Mcl-1L/Noxa complexes were highly increased, Mcl-1/Bak complexes were disrupted, and there was an accumulation of free Noxa. Finally, we observed a dissociation of Mcl-1/Bim complexes that may be due to a displacement of Bim induced by Noxa. Thus, in myeloma cells, the mechanistic basis for bortezomib sensitivity can be explained mainly by the model in which the sensitizer Noxa can displace Bim, a BH3-only activator, from Mcl-1, thus leading to Bax/Bak activation.
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PMID:Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. 1754 23

Cellular FLIP (cFLIP) is a homologue of caspase-8 without protease activity that inhibits the apoptosis signaling initiated by death receptor ligation. We previously reported that a long form of cFLIP (cFLIP-L) inhibits ubiquitylation of beta-catenin and enhances Wnt signaling. Here we show that cFLIP-L impairs the function of the ubiquitin-proteasome system (UPS), and increases the accumulation of various short-lived proteins, such as GFP conjugated with destabilization sequence, beta-catenin and HIF1 alpha, that are subjected to rapid ubiquitylation and degradation by proteasomes. Accordingly, beta-catenin- and HIF1 alpha-mediated gene expressions are induced in the cFLIP-L-expressing cells. Exogenously expressed cFLIP-L accumulates in aggregates at the peri-nuclear region in the cells, and the cFLIP-L aggregates are refractory to solubilization. Like exogenously expressed cFLIP-L, the endogenous cFLIP in A549 lung cancer cells displays particulate distribution in the cells and more than 60% of cFLIP-L is refractory to solubilization. Down-regulation of cFLIP in A549 cells by RNA-mediated interference reduced beta-catenin- and HIF1 alpha-mediated gene expression. These results suggest that cFLIP-L is prone to aggregate and impairs UPS function, which could be involved in the pathological function of cFLIP-L expressed in certain cancer cells.
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PMID:Impairment of the ubiquitin-proteasome system by cellular FLIP. 1757 74

EWS-Fli1 plays important roles in oncogenesis of Ewing's family tumors (EFTs). We have reported that EWS-Fli1 inhibits p21(waf1/cip1) and p27(kip1) expressions, which are degraded by the ubiquitin-proteasome pathway. Bortezomib efficiently up-regulated p21(waf1/cip1) and p27(kip1) expression, and induced apoptosis accompanied by the expression of cleaved-PARP, DR4 and activated caspase-8 in EFT cells. Since most EFTs deaths result from the tumor being resistant to chemotherapeutic drugs, the effects of novel anti-tumor reagents on drug-resistant tumors were next investigated. The results demonstrated that the drug-resistant EFT clones were cross-resistant to bortezomib probably due to the over-expression of the efflux pumps, P-glycoprotein and MRP1. We further investigated whether the efflux pump inhibitors would modulate the effects of bortezomib. The combination of P-gp-specific or MRP1-specific inhibitors could enhance the anti-tumor effects of bortezomib on the drug-resistant clones. These data suggest that bortezomib might be a substrate of P-gp and MRP1. Although bortezomib would be effective on the primary EFTs, it is necessary to pay attention to the resistance to bortezomib in clinical trials for the advanced cases. The combination of bortezomib and the efflux pump inhibitors might be a promising method as a novel molecular target therapy for advanced EFTs.
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PMID:The mechanism of cross-resistance to proteasome inhibitor bortezomib and overcoming resistance in Ewing's family tumor cells. 1778 11

The novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) induces apoptosis of cancer cells, enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and exhibits potent anticancer activity in animal models with a favorable pharmacokinetic profile. Thus, CDDO-Me is being tested in Phase I clinical trials. In an effort to understand the mechanism by which CDDO-Me induces apoptosis, particularly in human lung cancer cells, we previously demonstrated that CDDO-Me induces apoptosis involving c-Jun N-terminal kinase (JNK)-dependent upregulation of death receptor 5 (DR5) expression. In the current work, we determined the modulatory effects of CDDO-Me on the levels of c-FLIP, a major inhibitor of death receptor-mediated caspase-8 activation, and its impact on CDDO-Me-induced apoptosis and enhancement of TRAIL-induced apoptosis in human lung cancer cells. CDDO-Me rapidly and potently decreased c-FLIP levels including both long (FLIP(L)) and short (FLIP(S)) forms of c-FLIP in multiple human lung cancer cell lines. The presence of the proteasome inhibitor MG132, but not the JNK inhibitor SP600125, prevented CDDO-Me-induced c-FLIP reduction. Moreover, CDDO-Me increased ubiquitination of c-FLIP. Thus, CDDO-Me induces ubiquitin/proteasome-dependent c-FLIP degradation independently of JNK activation. Importantly, overexpression of c-FLIP (e.g., FLIP(L)) protected cells not only from CDDO-Me-induced apoptosis, but also from induction of apoptosis by the combination of CDDO-Me and TRAIL. Accordingly, silencing of c-FLIP with c-FLIP siRNA sensitized cancer cells to CDDO-Me. Collectively, these results indicate that c-FLIP downregulation contributes to CDDO-Me-initiated apoptosis and also to enhancement of TRAIL-induced apoptosis by CDDO-Me.
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PMID:c-FLIP downregulation contributes to apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) in human lung cancer cells. 1825 90


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