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)

To examine whether the tumor microenvironment alters cytokine-induced cytotoxicity, human prostate adenocarcinoma DU-145 cells were exposed to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or glucose deprivation, a common characteristic of the tumor microenvironment. TRAIL alone reduced cell survival in a dose-dependent manner. Glucose deprivation alone induced no cytotoxicity within 4 h. However, the combination of TRAIL (50 ng/ml) and glucose deprivation for 4 h increased cell death and PARP cleavage by promoting activation of caspase-8 and caspase-3, relative to that of TRAIL alone. Similar results were observed in human colorectal carcinoma CX-1 cells. Data from immunoblotting analysis reveal that glucose deprivation-enhanced TRAIL cytotoxicity is inversely related to the intracellular level of FLICE inhibitory protein (FLIP) but not that of death receptor 5 (DR5). Results from mass spectrometry show that glucose deprivation elevates ceramide. The elevation of ceramide may cause dephosphorylation of Akt and maintain dephosphorylation of Akt in the presence of TRAIL and then subsequently down-regulate the expression of FLIP. Taken together, the present studies suggest that glucose deprivation enhances TRAIL-induced cytotoxicity through the ceramide-Akt-FLIP pathway.
 ...
PMID:Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide-Akt-FLIP pathway. 1182 46

The nonsteroidal anti-inflammatory drugs (NSAIDs) are believed to mediate their anticancer effects by inducing apoptosis but the molecular mechanisms of their apoptotic effects remain largely unknown. Here we report that two different NSAIDs, sulindac sulfide and SC-'236 engage the death receptor 5 (DR5) and mitochondrial pathways to mediate apoptosis in human colon cancer cells. We show that sulindac sulfide and SC-'236-induced apoptosis is coupled with upregulation of DR5, caspase 8 activation and Bid cleavage. Thus, a cross talk appears to exist between the DR5 and mitochondrial pathways during apoptosis induced by these NSAIDs. We further show that sulindac sulfide and SC-'236-induced DR5 upregulation occurs independent of the COX inhibitory effects of these NSAIDs. Using Bax-proficient (Bax+/-) and Bax-deficient (Bax-/-) HCT116 human colon cancer cells, we further demonstrate that Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac sulfide and SC-'236. For example, sulindac sulfide upregulates DR5 in both Bax-deficient and proficient cells, but Apo2L/TRAIL efficiently potentiates sulindac sulfide-induced apoptosis as well as activation of caspase-8, -9 and -3 only in Bax-proficient cells. SC-'236 also upregulates DR5 in both Bax-proficient and Bax-deficient cells but Apo2L/TRAIL potentiates SC-'236-mediated apoptosis and caspases-8 and -3 activation in both Bax-proficient and Bax-deficient cells. Further, in Bax-deficient cells, neither sulindac sulfide nor SC-'236 in combination with Apo2L/TRAIL effectively promotes the release of cytochrome c from mitochondria into cytosol and caspase-9 activation. Collectively, our results suggest that unlike sulindac sulfide, SC-'236 in combination with Apo2L/TRAIL can overcome Bax deficiency to induce apoptosis. These results have important clinical implications in that the tumors harboring Bax mutations are likely to develop resistance to sulindac but not to SC-'236-like NSAIDs. In conclusion, the data presented herein form the basis of future in-depth studies to further explore the utility of Apo2L/TRAIL and NSAIDs, in combination, as a novel cancer preventive/therapeutic strategy.
 ...
PMID:Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac and a COX-2 selective non-steroidal anti-inflammatory agent in Bax-deficient cells. 1220 15

2-Methoxyestradiol (2ME2), a natural metabolite of estradiol, is a potent antitumor and antiangiogenic agent. In vitro, 2ME2 inhibits the proliferation of a wide variety of cell lines and primary cultures, and in numerous models in vivo, it has been shown to be an effective inhibitor of tumor growth and angiogenesis. 2ME2 is currently in several Phase I and Phase II clinical trials under the name Panzem. Although various molecular targets have been proposed for this compound, the mechanism by which 2ME2 exerts its effects is still uncertain. This study shows that 2ME2 uses the extrinsic pathway for induction of apoptosis. 2ME2 treatment results in up-regulation of death receptor 5 (DR5) protein expression in vitro and in vivo and renders cells more sensitive to the cytotoxic activities of the DR5 ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). 2ME2-induced apoptosis requires caspase activation and kinetic studies show the sequential activation of caspase-8, caspase-9, and caspase-3. Blockage of death receptor signaling by expression of dominant-negative Fas-associated death domain severely attenuates the ability of 2ME2 to induce apoptosis. Because 2ME2 administration has not manifested dose-limiting toxicity in the clinic, DR5 expression may serve as a surrogate marker for biological response.
 ...
PMID:2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway. 1254 4

Many malignant glioma cells express death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL-induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase-8-initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild-type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to downregulate caspase-8 inhibitor c-FLIP(S) (the short form of cellular Fas-associated death domain-fike interleukin-1-converting enzyme-inhibitory protein) and up-regulate Bak, a pro-apoptotic Bcl-2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.
 ...
PMID:TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways. 1465 59

Specific activation of apoptosis in tumor cells offers a promising approach for cancer therapy. Induction of apoptosis leads to activation of specific proteases. Two major pathways for caspase activation in mammalian cells have been described. One apoptotic pathway involves members of the tumor necrosis factor family of cytokine receptors (eg death receptor 5 (DR5)). The other pathway is controlled by the Bcl-2 family of proteins. The purpose of this study was to investigate whether increased apoptosis occurs in human glioma cells following infection with a recombinant adenoviral vector encoding the human Bax gene under the control of human vascular endothelial growth factor (VEGF) promoter element (AdVEGFBax) in combination with an anti-human DR5 monoclonal antibody (TRA-8). Specific overexpression of exogenous Bax protein induced apoptosis and cell death in glioma cell lines, through activation of both caspase-8 and -9, leading to activation of downstream caspase-3. The relative sensitivity to AdVEGFBax for the glioma cell lines was U251MG>U373MG>U87MG>D54MG. The recently characterized TRA-8 monoclonal antibody induces apoptosis of most TRAIL-sensitive tumor cells by specific binding to DR5 receptors on the cellular membrane. TRA-8 induced rapid apoptosis and cell death in glioma cells, but did not demonstrate detectable cytotoxicity of primary normal human astrocytes. The efficiency of TRA-8-induced apoptosis was variable in different glioma cell lines. The relative sensitivity to TRA-8 was U373MG>U87MG>U251MG>D54MG. The combination of TRA-8 treatment and overexpression of Bax overcame TRA-8 resistance of glioma cells in vitro. Cell viability of U251MG cells was 71.1% for TRA-8 (100 ng/ml) alone, 75.9% for AdVEGFBax (5 MOI) alone and 41.1% for their combination as measured by MTS assay. Similar enhanced apoptosis results were obtained for the other glioma cell lines. In vivo studies demonstrated that the combined treatment significantly (P<0.05) suppressed the growth of U251MG xenografts and produced 60% complete tumor regressions without recurrence. These data suggest that the combination of TRA-8 treatment with specific overexpression of Bax using AdVEGFBax may be an effective approach for the treatment of human malignant gliomas.
 ...
PMID:Enhanced apoptosis following treatment with TRA-8 anti-human DR5 monoclonal antibody and overexpression of exogenous Bax in human glioma cells. 1497 47

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.
 ...
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

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for cancer therapeutics. However, some tumor cells are resistant to TRAIL-induced apoptosis. Our previous studies have shown that luteolin, a naturally occurring flavonoid, induces the up-regulation of death receptor 5 (DR5), which is a receptor for TRAIL. Here, we show for the first time that luteolin synergistically acts with exogenous soluble recombinant human TRAIL to induce apoptosis in HeLa cells, but not in normal human peripheral blood mononuclear cells. The combined use of luteolin and TRAIL induced Bid cleavage and the activation of caspase-8. Also, human recombinant DR5/Fc chimera protein, caspase inhibitors, and DR5 siRNA efficiently reduced apoptosis induced by co-treatment with luteolin and TRAIL. These results raise the possibility that this combined treatment with luteolin and TRAIL might be promising as a new therapy against cancer.
 ...
PMID:The combination of TRAIL and luteolin enhances apoptosis in human cervical cancer HeLa cells. 1596 48

Luteolin, a naturally occurring flavonoid, induces apoptosis in various cancer cells. Little is known however concerning the underlying molecular mechanisms responsible for this activity. In this report, we reveal a novel mechanism by which luteolin-induced apoptosis occurs, and show for the first time that the apoptosis by luteolin is mediated through death receptor 5 (DR5) upregulation. Luteolin markedly induced the expression of DR5, along with Bcl-2-interacting domain cleavage and the activation of caspase-8, -10, -9 and -3. In addition, suppression of DR5 expression with siRNA efficiently reduced luteolin-induced caspase activation and apoptosis. Human recombinant DR5/Fc also inhibited luteolin-induced apoptosis. On the other hand, luteolin induced neither DR5 protein expression nor apoptosis in normal human peripheral blood mononuclear cells. These results suggest that DR5 induced by luteolin plays a role in luteolin-induced apoptosis, and raises the possibility that treatment with luteolin might be promising as a new therapy against cancer.
 ...
PMID:Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. 1600 31

Activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), results in up-regulation of not only antiapoptotic genes but also proapoptotic genes, including death receptor 4 (DR4) and death receptor 5 (DR5). Therefore, NF-kappaB activation either suppresses or promotes apoptosis depending on the type of stimulus or cell context. We showed previously that the synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), effectively induces apoptosis particularly in androgen-independent prostate carcinoma cells. This effect was associated with the ability of CD437 to induce the expression of DR4 and DR5. In the present study, we examined the hypothesis that NF-kappaB activation plays a role in CD437-induced death receptor expression and apoptosis. Treatment of DU145 cells with CD437 resulted in a rapid decrease (> or = 3 hours) of IkappaBalpha, which was accompanied by increased translocation of the NF-kappaB subunit p65 from the cytoplasm to the nucleus and increased NF-kappaB DNA-binding activity (> or = 4 hours). The NF-kappaB inhibitor, helenalin, inhibited CD437-induced IkappaBalpha reduction and p65 nuclear translocation. Accordingly, it also abrogated CD437-induced up-regulation of DR4, activation of caspase-8 and caspase-3, and increased DNA fragmentation. Overexpression of an IkappaBalpha dominant-negative mutant blocked not only CD437-induced p65 nuclear translocation but also DR4 up-regulation, caspase activation, and DNA fragmentation. CD437 was unable to decrease IkappaBalpha protein levels and up-regulate DR4 expression in CD437-resistant DU145 cells. Moreover, knockdown of Fas-associated death domain, caspase-8, and DR4, respectively, suppressed CD437-induced apoptosis. Collectively, these results indicate that CD437 activates NF-kappaB via decreasing IkappaBalpha protein and thereby induces DR4 expression and subsequent apoptosis in DU145 cells.
 ...
PMID:Activation of nuclear factor-kappaB contributes to induction of death receptors and apoptosis by the synthetic retinoid CD437 in DU145 human prostate cancer cells. 1602 38

Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L). In this study, we showed that tunicamycin, a naturally occurring antibiotic, is a potent enhancer of TRAIL-induced apoptosis through up-regulation of DR5 expression. Tunicamycin significantly sensitized PC-3, androgen-independent human prostate cancer cells, to TRAIL-induced apoptosis. The tunicamycin-mediated enhancement of TRAIL-induced apoptosis was markedly blocked by a recombinant human DR5/Fc chimeric protein. Tunicamycin and TRAIL cooperatively activated caspase-8, -10, -9, and -3 and Bid cleavage and this activation was also blocked in the presence of the DR5/Fc chimera. Tunicamycin up-regulated DR5 expression at the mRNA and protein levels in a dose-dependent manner. Furthermore, the tunicamycin-mediated sensitization to TRAIL was efficiently reduced by DR5 small interfering RNA, suggesting that the sensitization was mediated through induction of DR5 expression. Tunicamycin increased DR5 promoter activity and this enhanced activity was diminished by mutation of a CHOP-binding site. In addition, suppression of CHOP expression by small interfering RNA reduced the tunicamycin-mediated induction of DR5. Of note, tunicamycin-mediated induction of CHOP and DR5 protein expression was not observed in normal human peripheral blood mononuclear cells. Moreover, tunicamycin did not sensitize the cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may be a promising candidate for prostate cancer therapy.
 ...
PMID:Tunicamycin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human prostate cancer cells. 1602 39


1 2 3 4 5 6 7 8 9 Next >>