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)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert potent cytotoxic activity against many tumor cells but not normal cells. However, some tumor cells are resistant to TRAIL, and it has not been determined how this occurs. In the present study, we obtained three subgroups of Jurkat clones with TRAIL-sensitive, -partial resistant and -resistant phenotypes. We found that most TRAIL-resistant and -partial resistant clones expressed low levels of DR5, whereas most TRAIL-sensitive clones expressed high levels of Death Receptor (DR5). However, there were clones with a range of different TRAIL-sensitivities that had similar levels of DR5 expression. The expression levels of DR4 and the decoy receptors, DcR1 and DcR2, did not correlate with TRAIL sensitivities. We also compared the subgroups in terms of the expression of Fas-associated death domain protein (FADD), the levels of activation of Receptor Interacting Protein (RIP) and caspases, and cleavage of Poly (ADP-Ribose)Polymerase (PARP). Basal expression levels of FADD were not significantly different among the subgroups. After treatment with TRAIL, both TRAIL-sensitive and partial resistant clones showed high levels of activation of caspase-3, caspase-8, RIP and PARP. Relative basal level and induced level of Phosphoprotein over Expressed in Diabetes/Phosphoprotein Enriched in Astrocytes (PED/PEA-15) after TRAIL treatment were compared in the clones. Basal levels of PED/PEA-15 expression were similar among sensitive, partial resistant and resistant clones. TRAIL did not change the PED/PEA-15 level in the clones. In addition, transduction and expression of the dominant negative form of the I-kBalpha gene did not change TRAIL-sensitivities. Our results showed that the expression levels of DR5, the activation levels of caspase-8, -3 and RIP were critical factors in determining TRAIL-sensitivities in Jurkat cells. The results of our study also suggest that cells with different TRAIL-sensitivities arise through multiple mechanisms even within a single cell line.
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PMID:Analysis of the phenotypes of Jurkat clones with different TRAIL-sensitivities. 1270 64

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to trigger apoptosis in many malignant cells. Whereas cancer cells are responsive to TRAIL-induced cell death when used alone or in combination with other agents, normal cells are known to be relatively less sensitive to the ligand, making it a desirable therapeutic compound to target a variety of cancers. TRAIL induces apoptosis through its interaction with its two proapoptotic death receptors (DRs), DR4 and DR5. In addition, it may also bind the decoy receptors (DcRs), DcR1 and DcR2, which lack an intracellular signaling domain, thus negatively regulating TRAIL-induced apoptosis. Previously, it has been shown that interleukin (IL)-8 is elevated in the ascites of patients with ovarian cancer. Therefore, we examined the role that IL-8 may play in modulating sensitivity to TRAIL-mediated apoptosis. We treated the TRAIL-sensitive cell line OVCAR3 with TRAIL over a period of time with or without pretreatment with IL-8. Here we show the novel findings that IL-8 blocks TRAIL-induced cell death and was able to turn the TRAIL-sensitive cell line into a TRAIL-resistant one. We hypothesized that decreased expression of DRs DR4 and DR5 may contribute to TRAIL resistance. Both reverse transcription-PCR and flow cytometry revealed a decrease in DR4 expression after pretreatment of OVCAR3 cells with IL-8. We have also shown that TRAIL was able to induce caspase-8 cleavage in these cells, whereas pretreatment with IL-8 blocked this caspase cleavage. Through array analysis and confirmation with other techniques, we have determined that IL-8 regulates the expression of a member of the mitogen-activated protein kinase superfamily, p38gamma. These findings provide important insights into the modulation of apoptosis by TRAIL and IL-8 in ovarian cancer. The data suggest a potentially important role of IL-8 in protecting ovarian cancer cells from TRAIL-mediated apoptosis and signify a new potential chemotherapeutic target to augment TRAIL therapy.
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PMID:Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3. 1290 26

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis. Although chemotherapy treatment did not modulate mRNA or cell surface expression of the TRAIL receptors death receptor 4, death receptor 5, decoy receptor 1, or decoy receptor 2, it was found to down-regulate expression of the caspase-8 inhibitor, c-FLIP. Stable overexpression of the long c-FLIP splice form but not the short form was found to inhibit chemotherapy/rTRAIL-induced apoptosis. Furthermore, siRNA-mediated down-regulation of c-FLIP, particularly the long form, was found to sensitize colon cancer cells to rTRAIL-induced apoptosis. In addition, treatment of a 5-FU-resistant cell line with 5-FU down-regulated c-FLIP expression and sensitized the chemotherapy-resistant cell line to rTRAIL. We conclude that TRAIL-targeted therapies may be used to enhance conventional chemotherapy regimens in colon cancer regardless of tumor p53 status. Furthermore, inhibition of c-FLIP may be a vital accessory strategy for the optimal use of TRAIL-targeted therapies.
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PMID:Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP. 1637 18

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds great potential as an anticancer drug, since it induces selective cell death in cancer cells but not in normal ones. However, cancer cells often acquire resistance to TRAIL, which hinders its clinical efficacy. We previously demonstrated that progesterone triggers apoptosis in human ovarian cancer (OCa) cells. In the present study, we evaluated the prospect of utilizing progestins in combination with TRAIL to enhance cell death in TRAIL-sensitive (OVCA 420, OVCA 429, and OVCA 433) and -resistant (OVCA 432) OCa cell lines. TRAIL sensitivity (60-80% cell kill) bore no correlation with expression of the TRAIL receptors (DR4, DR5) or their decoys (DcR1 and DcR2), but was associated with activation of caspase-8 and -3, and downregulation of the long isoform of FLICE-like inhibitory protein (c-FLIP(L)), an anti-apoptosis mediator. Small interfering RNA-mediated knockdown of c-FLIP(L) expression restored TRAIL sensitivity in OVCA 432 cells. Induction of c-FLIP(L) overexpression increased TRAIL resistance in TRAIL-sensitive lines. Thus, persistent high level of c-FLIP(L) expression likely mediates TRAIL resistance in OCa cells. Treatment of OCa cells with progesterone enhanced TRAIL-induced cell death (>85%), but only in TRAIL-sensitive cell lines. Combined treatment with two progestins was superior to single progestin treatment, with progesterone plus medroxyprogesterone acetate (MPA) achieving over 85% cell kill in both TRAIL-sensitive and -resistant OCa cell lines. Significantly, unlike TRAIL, progestin-induced cell death did not involve c-FLIP(L) downregulation. Hence, combined progestin regimens, with or without TRAIL, may serve as an effective therapy for OCa by circumventing the anti-apoptotic action of c-FLIP(L).
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PMID:Progesterone induces apoptosis in TRAIL-resistant ovarian cancer cells by circumventing c-FLIPL overexpression. 1739 32

The improved recombinant form of the death ligand Apo2L/TRAIL (Apo2L/TRAIL.0) is not cytotoxic for normal human cells and is a good candidate for the therapy of multiple myeloma (MM), a B-cell neoplasia that remains incurable. We have analyzed the molecular determinants of myeloma sensitivity to Apo2L/TRAIL.0 in a number of MM cell lines, the mechanisms of resistance and a possible way of overcoming it. Expression of one death receptor for Apo2L/TRAIL (DR4 or DR5) is sufficient to transduce death signals, though DR5 was more efficient when both receptors were present. Membrane expression of decoy receptors (DcR1, DcR2) and intracellular levels of c-FLIP(L), XIAP and Mcl-1 were not predictive of resistance to Apo2L/TRAIL. Inhibition of Mcl-1 degradation did not prevent Apo2L/TRAIL-induced apoptosis. In IM-9 cells, resistance was associated to a reduced caspase-8 expression. U266 cells, though expressing significant levels of DR4 and caspase-8, were nevertheless resistant to Apo2L/TRAIL. This resistance could be overcome by co-treatment with valproic acid (VPA), a histone deacetylase inhibitor. VPA caused the redistribution of DR4 to plasma membrane lipid rafts and restored DR4 signaling. Overexpression of Mcl-1 in U266 cells did not prevent Apo2L/TRAIL cytotoxicity in VPA-sensitized cells. These results, taken together, support the possible use of Apo2L/TRAIL.0 in the treatment of MM.
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PMID:Membrane expression of DR4, DR5 and caspase-8 levels, but not Mcl-1, determine sensitivity of human myeloma cells to Apo2L/TRAIL. 1746 28

The number and activity of osteoclasts (OCs) are critical for maintaining normal bone turnover. The number is determined by the rates of cell differentiation and death. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis by interacting with its death receptors, (DR4, DR5). However, its activity can be modulated by two decoy receptors, (DcR1 and DcR2). In this paper we show that TRAIL treatment causes reduced OC viability as well as an increased apoptotic OC number. Loss of nuclei integrity and derangement of the actin microfilament were also induced by TRAIL in OCs. Moreover, we demonstrated the expression of all TRAIL receptors in both precursors and differentiated OCs, and the upregulation of DR5 during OC differentiation. Interestingly, DcR2 was upregulated in the early stage of osteoclastogenesis and downregulated at the end of the differentiation process. We showed that DR5, upregulated by TRAIL, could be the mediator of TRAIL-induced OC apoptosis, since the addition of anti-DR5 neutralizing antibodies restores the OC viability previously reduced by TRAIL. Furthermore, the intracellular pathway induced by TRAIL in OCs involves caspase-8 and Bid activation. In conclusion, our data highlight an important role for the TRAIL/TRAIL receptor system in the regulation of OC apoptosis.
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PMID:The death receptor DR5 is involved in TRAIL-mediated human osteoclast apoptosis. 1755 61

Tryptophol is a natural component isolated from vinegar produced from the boiled extract of black soybean. We have reported that tryptophol induces apoptosis in U937 cells via activation of caspase-8 followed by caspase-3. Tryptophol, however, did not affect human peripheral blood lymphocytes (PBL). In this study, we found that tryptophol enhances formation of a death-inducing signaling complex including death receptor (DR) 5. Cell viability and induction of apoptosis by tryptophol was reduced by transfection with decoy receptor (DcR) 1. These results indicate that tryptophol induces apoptosis through DR5 and that the resistance of PBL to tryptophol-induced apoptosis might be due to competition from DcR1.
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PMID:Tryptophol induces death receptor (DR) 5-mediated apoptosis in U937 cells. 1769 Apr 53

We demonstrate that blockade of the MEK/ERK signaling module, using the small-molecule inhibitors PD184352 or PD325901 (PD), strikingly enhances arsenic trioxide (ATO)-induced cytotoxicity in human myeloma cell lines (HMCLs) and in tumor cells from patients with multiple myeloma (MM) through a caspase-dependent mechanism. In HMCLs retaining a functional p53, PD treatment greatly enhances the ATO-induced p53 accumulation and p73, a p53 paralog, cooperates with p53 in caspase activation and apoptosis induction. In HMCLs carrying a nonfunctional p53, cotreatment with PD strikingly elevates the (DR4 + DR5)/(DcR1 + DcR2) tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors ratio and caspase-8 activation of ATO-treated cells. In MM cells, irrespective of p53 status, the combined PD/ATO treatment increases the level of the proapoptotic protein Bim (PD-mediated) and decreases antiapoptotic protein Mcl-1 (ATO-mediated). Moreover, Bim physically interacts with both DR4 and DR5 TRAIL receptors in PD/ATO-treated cells, and loss of Bim interferes with the activation of both extrinsic and intrinsic apoptotic pathways in response to PD/ATO. Finally, PD/ATO treatment induces tumor regression, prolongs survival, and is well tolerated in vivo in a human plasmacytoma xenograft model. These preclinical studies provide the framework for testing PD325901 and ATO combination therapy in clinical trials aimed to improve patient outcome in MM.
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PMID:Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. 1858 68

Periodontal disease (Pd) is characterized by an increased osteoclast resorption and a decreased osteoblast (OB) bone formation. OBs obtained from alveolar bone of Periodontitis patients (Pp) undergo apoptosis in the presence of TNF-related apoptosis-inducing ligand (TRAIL). We studied the intracellular apoptotic pathway induced by TRAIL; TRAIL death (DR4, DR5) and decoy (DcR1, DcR2) receptors expression in Periodontitis patients OBs (PpOBs), and we measured the concentration of TRAIL in the serum of Pp. We demonstrated that DNA fragmentation and activation of caspase-8 and caspase-3 in PpOBs, following TRAIL stimulation, occurred in shorter time; moreover, a higher amount of both caspases was activated in order to direct OBs. Down-regulation of DcR2 in PpOBs was demonstrated and high TRAIL levels were detected in the serum of Pp. In conclusion, our data suggest that PpOBs are more sensitive to TRAIL-induced apoptosis when compared to the control group. The down-regulation of DcR2 possibly leads to an imbalanced ratio between death and decoy receptors. Our findings highlight a role of TRAIL in the pathogenesis of Pd.
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PMID:Osteoblast apoptosis in periodontal disease: role of TNF-related apoptosis-inducing ligand. 1930 56

To explore the molecular mechanisms by which glioblastomas are resistant to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), we examined TRAIL signalling pathways in the tumours. TRAIL has four membrane-anchored receptors, death receptor 4/5 (DR4/5) and decoy receptor 1/2 (DcR1/2). Of these receptors, only DR5 was expressed consistently in glioblastoma cell lines and tumour tissues, ruling out the role of DcR1/2 in TRAIL resistance. Upon TRAIL binding, DR5 was homotrimerized and recruited Fas-associated death domain (FADD) and caspase-8 for the assembly of death-inducing signalling complex (DISC) in the lipid rafts of the plasma membrane. In the DISC, caspase-8 was cleaved and initiated apoptosis by cleaving downstream caspases in TRAIL-sensitive glioblastoma cells. In TRAIL-resistant cells, however, DR5-mediated DISC was modified by receptor-interacting protein (RIP), cellular FADD-like interleukin-1beta-converting enzyme inhibitory protein (c-FLIP) and phosphoprotein enriched in diabetes or in astrocyte-15 (PED/PEA-15). This DISC modification occurred in the non-raft fractions of the plasma membrane and resulted in the inhibition of caspase-8 cleavage and activation of nuclear factor-kappaB (NF-kappaB). Treatment of resistant cells with parthenolide, an inhibitor of inhibitor of kappaB (I-kappaB), eliminated TRAIL-induced NF-kappaB activity but not TRAIL resistance. In contrast, however, targeting of RIP, c-FLIP or PED/PEA-15 with small interfering RNA (siRNA) led to the redistribution of the DISC from non-rafts to lipid rafts and eliminated the inhibition of caspase-8 cleavage and thereby TRAIL resistance. Taken together, this study indicates that the DISC modification by RIP, c-FLIP and PED/PEA-15 is the most upstream event in TRAIL resistance in glioblastomas.
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PMID:DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas. 1943 16


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