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)

Tumor necrosis factor receptor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis primarily in cancer cells with little or no effect on normal cells; therefore, it has the potential for use in cancer therapy. TRAIL binding to death receptors DR4 and DR5 triggers the death-inducing signal complex formation and activation of procaspase-8, which in turn activates caspase-3, leading to cell death. Like FasL, TRAIL can trigger type 1 (caspase-8 --> caspase-3) or type 2 (caspase-8 --> Bid cleavage --> capsase-9 --> caspase-3) apoptotic pathways depending on the cell type. Some cancers are resistant to TRAIL treatment because most molecules in the TRAIL signaling pathway, including FLIPs and IAPs, can contribute to resistance. In addition, we have identified an essential role for splice variants of the IG20 gene in TRAIL resistance.
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PMID:Role of IG20 splice variants in TRAIL resistance. 1822 7

As human colorectal cancer (CRC) cells metastasize to distant sites, they are susceptible to detachment-induced cell death or anoikis - a form of apoptosis that occurs when anchorage-dependent CRC cells go into suspension. Our goal was to identify whether tumor necrosis factor receptor apoptosis-inducing ligand (TRAIL) receptors mediate anoikis in human CRC cells. First, we assessed whether caspases of the extrinsic (caspase-8) or intrinsic (caspase-9) death pathways were involved. Caspase-8 was cleaved during exposure to suspension culture in four CRC lines, and cell death was inhibited by caspase-3 and caspase-8 inhibitors but not by a caspase-9 inhibitor. Gene transcripts in macrophage inflammatory protein-101 (MIP-110), a weakly metastatic human CRC, were increased at least 2-fold for TRAIL-R2 (DR5) and TRAIL after 24 h of suspension culture compared with cells in monolayer culture. The increased expression of DR5 was confirmed at the protein level at 24 h, and exposure of MIP-101 cells to an antagonistic antibody to DR5 decreased caspase-8 activation. The antagonistic antibody to DR5 inhibited anoikis in four human CRC lines. Treatment with an antagonistic DR4 antibody or a neutralizing antibody to TRAIL ligand did not reduce anoikis consistently. Knockdown of DR5 or TRAIL also inhibited anoikis, whereas exogenous TRAIL or FasL did not consistently increase anoikis. In summary, DR5 receptor mediates death signals for anoikis in human CRC cells through the extrinsic apoptotic pathway.
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PMID:DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. 1824 94

Acetyl-keto-beta-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 microg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage. The activation of caspase-8 was correlated with increased levels of death receptor (DR) 5 but not of Fas or DR4. AKBA-induced apoptosis, caspase-8 activation, and PARP cleavage were inhibited by knocking down DR5 using a small hairpin RNA. AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP.
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PMID:Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. 1828 94

Androgen withdrawal induces the regression of human prostate cancers, but such cancers eventually become androgen-independent and metastasize. Thus, deciphering the mechanism of androgen withdrawal-induced apoptosis is critical to designing new therapies for prostate cancer. Previously, we showed that in the rat, castration-induced apoptosis is accompanied by a reduction in the expression of the apical caspase inhibitor FLICE-like inhibitory protein (FLIP). To test the functional role of FLIP in inhibiting prostate epithelial cell apoptosis, we employed the rat prostate epithelial cell line NRP-152, which differentiates to a secretory phenotype in a low-mitogen medium and then undergoes apoptosis following the addition of transforming growth factor beta1 (TGFbeta1), mimicking androgen withdrawal-induced apoptosis. FLIP levels decline with TGFbeta1 treatment, suggesting that apoptosis is mediated by caspase-8 and indeed the caspase inhibitor crmA blocks TGFbeta1-induced apoptosis. Small interfering RNA-mediated knockdown of FLIP recapitulates and enhances TGFbeta1-induced cell death. NRP-152 cells stably transfected with constitutively expressed FLIP were refractory to TGFbeta1-induced apoptosis. TGFbeta1-induced caspase-3 activity is proportional to the level of cell death and inversely proportional to the level of FLIP expression in various clones. Moreover, neither caspase-3 nor PARP is cleaved in clones expressing high levels of FLIP. Furthermore, insulin, which inhibits differentiation, increases FLIP and inhibits TGFbeta-induced death in a FLIP-dependent manner. Although neither Fas-Fc, sTNFRII-Fc, nor DR5-Fc blocked TGFbeta1-induced cell death, there is a significant increase in tumor necrosis factor mRNA following TGFbeta stimulation, suggesting both an unexpected role for tumor necrosis factor in this model system and the possibility that FLIP blocks another unknown caspase-dependent mediator of apoptosis.
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PMID:FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. 1831 84

Targeting TRAIL receptors with either recombinant TRAIL or agonistic DR4- or DR5-specific antibodies has been considered a promising treatment for cancer, particularly due to the preferential apoptotic susceptibility of tumor cells over normal cells to TRAIL. However, the realization that many tumors are unresponsive to TRAIL treatment has stimulated interest in identifying apoptotic agents that when used in combination with TRAIL can sensitize tumor cells to TRAIL-mediated apoptosis. Our studies suggest that various apoptosis defects that block TRAIL-mediated cell death at different points along the apoptotic signaling pathway shift the signaling cascade from default apoptosis toward cytoprotective autophagy. We also obtained evidence that inhibition of such a TRAIL-mediated autophagic response by specific knockdown of autophagic genes initiates an effective mitochondrial apoptotic response that is caspase-8-dependent. Currently, the molecular mechanisms linking disabled autophagy to mitochondrial apoptosis are not known. Our analysis of the molecular mechanisms involved in the shift from protective autophagy to apoptosis in response to TRAIL sheds new light on the negative regulation of apoptosis by the autophagic process and by some of its individual components.
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PMID:Involvement of protective autophagy in TRAIL resistance of apoptosis-defective tumor cells. 1837 89

Indirubin-3'-monoxime (I3M) is a derivative of indirubin, an active component from a Chinese medicinal recipe with known anti-cancer function. I3M has been well established as a cyclin-dependent kinase (CDK) inhibitor, while the molecular mechanism underlying I3M-induced apoptosis has not been fully elucidated. In this study, we focused on the critical role of the pro-apoptosis Bcl-2 family members in I3M-induced apoptosis. We first observed I3M-induced apoptosis in a time- and dose-dependent manner in three different types of human cancer cells-cervical cancer HeLa, hepatoma HepG2 and colon cancer HCT116. Induction of the caspase cascade for both the extrinsic and intrinsic pathways was demonstrated, including caspase-8, -9 and -3 activation. Initiation of the death receptor pathway started with enhanced surface expression of DR4 and DR5, as well as increased total protein level, which correlated with the up-regulation of p53 and its transcriptional activity. Importantly, we found in HeLa cells that caspase-8 activation resulted in Bid cleavage, followed by Bax conformational change and hence the amplification of the apoptotic signals through the mitochondrial pathway. Consistently, stable knockdown of Bid abrogated I3M-induced Bax conformational change and cell death. Moreover, ectopic expression of a viral caspase inhibitor (CrmA) or Bcl-2 partially protected I3M-induced apoptosis. In conclusion, our results indicate that I3M mainly elicites apoptosis through extrinsic pathway with type II response mediated by the pro-apoptotic Bcl-2 family members (Bid and Bax).
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PMID:Critical role of Bid and Bax in indirubin-3'-monoxime-induced apoptosis in human cancer cells. 1837 73

Synthetic triterpenoids 2-cyano-3, 12-dioxooleana-1, 9-(11)-dien-28-oic acid (CDDO) and CDDO-Me (CDDO-methyl ester) have entered clinical trials for cancer. We determined that CDDO analogues at submicromolar concentrations induce apoptosis of cultured prostate cancer cell lines, LNCaP, ALVA31, Du145, PC3, and PPC1, with lethal dose 50% approximately 1 micromol/L for CDDO-Me and an imidazole analogue (CDDO-Im). These compounds induced apoptosis of prostate cancer cells as characterized by cleavage of caspase-3, caspase-7, caspase-8, caspase-9, caspase-10, BID, and poly(ADP)ribose polymerase and by dependence on caspase activity. Moreover, triterpenoid-induced cell death was abolished by caspase-8-targeting small interfering (si) RNA. To explore the mechanism(s) involved in caspase-8 activation, we examined cell surface expression of death receptor (DR)4 and DR5 after triterpenoid treatment. Cell surface DR4 and DR5 expression was significantly up-regulated by CDDO or CDDO-Im but not by CDDO-Me. DR4 and DR5 knockdown with siRNA significantly inhibited apoptosis induced by CDDO and CDDO-Im but had no effect on CDDO-Me-induced killing, suggesting that CDDO and CDDO-Im induce apoptosis by a different mechanism than CDDO-Me. In addition to activating the caspase-8-dependent extrinsic apoptosis pathway, we observed that Bcl-X(L) overexpression inhibited triterpenoid-mediated killing of prostate cancer cell line Du145, suggesting that the intrinsic pathway (via mitochondria) also participates in triterpenoid-mediated killing. In vivo antitumor activity of CDDO-Me was shown using a Du145 tumor xenograft model in nude rats. Altogether, these findings suggest CDDO and related synthetic triterpenoids should be further evaluated as potential novel therapeutics for hormone refractory prostate cancers.
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PMID:Apoptotic activity and mechanism of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic-acid and related synthetic triterpenoids in prostate cancer. 1841 62

To investigate the combined effect of human recombinant soluble TNF-related apoptosis induced ligand (hrsTRAIL) with Ara-C or alone on HL-60 leukemia cell lines and its mechanism, human leukemia cell lines HL-60 were cultured in vitro. HL-60 cells were divided into 5 groups: control group, Ara-C group, rsTRAIL group, Ara-C + rsTRAIL simultaneously given group, Ara-C + rsTRAIL tandem given group (Ara-C followed by rsTRAIL group). The cytotoxic effect was measured by MTT assay; cell apoptosis rate was determined by flow cytometry after Annexin V/PI staining; the expression level of DR5 on surface of HL-60 cells treated with Ara-C at different concentrations for 24 hours was determined by flow cytometry. The expression level of DR5 on surface of HL-60 cells and caspase-8 activity in HL-60 cells of rsTRAIL group and Ara-C + rsTRAIL tandem group was determined by flow cytometry. The result showed that rsTRAIL could inhibit the proliferation of HL-60 cells and induce apoptosis of HL-60 cells in a concentration-dependent manner. The apoptosis rate of HL-60 cells in Ara-C + rsTRAIL tandem given group was higher than that in Ara-C + rsTRAIL simultaneously given group, the expression level of DR5 on surface of HL-60 cells and intracellular activity of caspase-8 in Ara-C + rsTRAIL tandem given group were higher than those in rsTRAIL group. When HL-60 cells treated with 5 and 10 mg/L of Ara-C for 24 hours, the expression level of DR5 on surface of HL-60 cells was higher than that in control group. It is concluded that rsTRAIL can inhibit the proliferation of HL-60 cells, and induce apoptosis of HL-60 cells. Ara-C can upregulate DR5 expression on the surface of HL-60 cells and enhance the effect of rsTRAIL-inducing apoptosis. Tandem treatment of HL-60 cells with Ara-C followed by rsTRAIL induce more apoptosis than that of co-treatment with rsTRAIL and Ara-C. Ara-C and rsTRAIL has a synergistic inhibitory effect on growth of HL-60 cells. The mechanism may correlate with up-regulation of the expression level of DR5 and/or caspase-8 in HL-60 cells by Ara-C.
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PMID:[Combined effect of TNF-related apoptosis induced ligand and Ara-C in inducing apoptosis of HL-60 cells and its mechanism]. 1854 19

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

Because Bcl-2 family members inhibit the ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis, we investigated whether ABT-737, a small molecule Bcl-2 inhibitor, enhances TRAIL killing. We demonstrate that a combination of ABT-737 and TRAIL induced significant cell death in multiple cancer types, including renal, prostate, and lung cancers, although each agent individually had little activity in these tumor cells. All of these cell lines expressed the Mcl-1 protein that is known to block the activity of ABT-737 and TRAIL but did not block the synergy between these agents. However, Bax-deficient cell lines, including DU145 and HCT116 cells and those cell lines expressing low levels of TRAIL receptor, were resistant to apoptosis induced by these agents. To understand how ABT-737 functions to markedly increase TRAIL sensitivity, the levels of specific death-inducing signaling complex components were evaluated. Treatment with ABT-737 did not change the levels of c-FLIP, FADD, and caspase-8 but up-regulated the levels of the TRAIL receptor DR5. DR5 up-regulation induced by ABT-737 treatment occurred through a transcriptional mechanism, and mutagenesis studies demonstrated that the NF-kappaB site found in the DR5 promoter was essential for the ability of ABT-737 to increase the levels of this mRNA. Using luciferase reporter plasmids, ABT-737 was shown to stimulate NF-kappaB activity. Together, these results demonstrate that the ability of ABT-737 and TRAIL to induce apoptosis is mediated through activation of both the extrinsic and intrinsic pathways. Combinations of ABT-737 and TRAIL can be exploited therapeutically where antiapoptotic Bcl-2 family members drive tumor cell resistance to current anticancer therapies.
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PMID:ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis. 1859 88

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