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)

A small-molecule mimetic of Smac/Diablo that specifically counters the apoptosis-inhibiting activity of IAP proteins has been shown to enhance apoptosis induced by cell surface death receptors as well as chemotherapeutic drugs. Survey of a panel of 50 human non-small-cell lung cancer cell lines has revealed, surprisingly, that roughly one-quarter of these lines are sensitive to the treatment of Smac mimetic alone, suggesting that an apoptotic signal has been turned on in these cells and is held in check by IAP proteins. This signal has now been identified as the autocrine-secreted cytokine tumor necrosis factor alpha (TNFalpha). In response to autocrine TNFalpha signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.
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PMID:Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. 1799 48

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib shows potent antitumor activity in some non-small-cell lung cancer (NSCLC) cell lines and is approved by the Food and Drug Administration as second and third line treatment for NSCLC. However, the molecular mechanisms by which erlotinib induces apoptosis remain to be elucidated. Here, we investigated the effect of erlotinib on apoptotic signal pathways in H3255 cells with the EGFR(L858R) mutation. Erlotinib induces apoptosis associated with the activation of caspases in a dose- and time-dependent manner. Erlotinib did not alter the expression of apoptotic receptors FAS and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although it induced caspase-8 activation and BID cleavage. In addition, cell death caused by erlotinib was not prevented by coincubation with FAS and TRAIL antagonists, ZB-4 monoclonal antibody and TRAIL/Fc recombinant, suggesting that erlotinib-induced apoptosis is not associated with receptor-mediated pathways. Erlotinib induces loss of mitochondrial membrane potential and release of cytochrome c and second mitochondria-derived activator of caspases/direct IAP binding protein with low pI from mitochondria. Furthermore, erlotinib causes BAX translocation to mitochondria, BAX and BAK conformational changes, and oligomerization. Erlotinib did not induce reactive oxygen species generation, and cotreatment with antioxidants did not alter erlotinib-induced activation of BAX and BAK and apoptosis. However, cotreatment with inhibitors of mitochondrial oxidative phosphorylation significantly blocked erlotinib-induced activation of BAX and BAK and cell death. Benzyloxycarbiny-VAD-fluoromethyl ketone had no effect on erlotinib-induced BAX and BAK activation but effectively prevented apoptosis. Overexpression of BCL-2 caused a significant attenuation of erlotinib-induced cell death, but no effect on BAX and BAK activation. Down-regulation of BAX and BAK gene expression with small interfering RNA led to an effective reduction of erlotinib-induced apoptosis. Our data indicate that activation of BAX and BAK plays a critical role in the initiation of erlotinib-induced apoptotic cascades.
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PMID:Erlotinib induces mitochondrial-mediated apoptosis in human H3255 non-small-cell lung cancer cells with epidermal growth factor receptorL858R mutation through mitochondrial oxidative phosphorylation-dependent activation of BAX and BAK. 2613 Feb 90

Smac mimetics (inhibitor of apoptosis [IAP] antagonists) are synthetic reagents that kill susceptible tumor cells by inducing degradation of cellular IAP (cIAP) 1 and cIAP2, nuclear factor kappaB activation, tumor necrosis factor (TNF) alpha production, TNF receptor 1 occupancy, and caspase-8 activation. In this issue of The Journal of Cell Biology, Vince et al. (see p. 171) report remarkable similarities in the events leading to tumor cell death triggered by the cytokine TWEAK (TNF-like weak inducer of apoptosis) and IAP antagonists. Although the mechanistic details differ, a common and necessary feature that is also shared by TNF receptor 2 signaling is reduction in the level of cIAP1 and, in some cases, cIAP2 and TNF receptor-associated factor 2. These findings not only extend our appreciation of how cell death pathways are kept in check in tumors, they reinforce the possible utility of induced cIDE (cIAP deficiency) in the selective elimination of neoplastic cells.
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PMID:TWEAKing death. 1860 50

The oncogenic process leading to nasopharyngeal carcinoma (NPC) requires the combination of genetic and epigenetic alterations, latent infection by the Epstein-Barr virus and local inflammation. A transcriptome analysis of NPC xenografts identified the gene encoding the cellular inhibitor of apoptosis protein 2 (c-IAP2) among the top five most intensely expressed. Consistently, the very high levels of the c-IAP2 protein were detected in 11 of 13 NPC biopsies. RMT 5265, a structural analog of second mitochondria-derived activator of caspase (SMAC), induced the rapid degradation of c-IAP2 in nasopharyngeal epithelial cells, whether malignant or not, but blocked clonal cell growth in NPC cells only. In short-term experiments, RMT 5265 induced apoptosis in a fraction of NPC cells, and this apoptosis was dramatically enhanced when RMT 5265 was combined with Toll-like receptor 3 (TLR3) stimulation. By contrast, the cooperative effect with tumor necrosis factor alpha was only marginal. The apoptosis induced by the combination of RMT 5265 and TLR3 stimulation was mediated by caspase-8 and associated with a decrease in the cellular content of the long isoform of FLICE-like inhibitory protein. Similar caspase-8 activation was obtained when siRNA knockdown of c-IAP2 was combined with TLR3 stimulation. In conclusion, c-IAP2 has a specific protective function in NPC cells challenged by TLR3 agonists. This protective function is probably important to make NPC cells tolerant to their own production of small viral RNAs, which are potential agonists of TLR3. Our data will help to design a rational use of IAP inhibitors in NPC patients.
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PMID:Recurrent overexpression of c-IAP2 in EBV-associated nasopharyngeal carcinomas: critical role in resistance to Toll-like receptor 3-mediated apoptosis. 1895 27

FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.
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PMID:XIAP discriminates between type I and type II FAS-induced apoptosis. 1993

This paper shows that the histone deacetylase inhibitor SAHA sensitised at sub-toxic doses human hepatocellular carcinoma cells (HepG2, Hep3B and SK-Hep1) to TRAIL-induced apoptosis, while it was ineffective in primary human hepatocytes (PHHs). In particular in HCC cells SAHA increased the expression of death receptor 5 (DR5) and caused a decrement of c-Flip. These two modifications provoked in the presence of TRAIL the rapid production of TRAIL-DISC and the activation of caspase-8. Consequently SAHA/TRAIL combination induced many apoptotic events, such as a cleavage of Bid into tBid, dissipation of mitochondrial membrane potential, activation of caspase-3 with the consequent cleavage of both NF-kB and Akt. The decrease in NF-kB level seemed to be responsible for the reduction in the content of IAP family antiapoptotic proteins while the decrease in Akt level caused a reduction in phospho-Bad. These events led to the activation of caspase-9, which contributed to the strong apoptotic activity of TRAIL. Sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by SAHA may suggest new strategies for the treatment of liver tumours.
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PMID:The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation. 1964

Extracellular adenosine disrupted mitochondrial membrane potentials in HuH-7 cells, a Fas-deficient human hepatoma cell line, and the effect was inhibited by the adenosine transporter inhibitor dipyridamole or by overexpressing Bcl-X(L). Adenosine downregulated the expression of mRNAs and proteins for Bcl-X(L) and inhibitor of apoptosis protein 2 (IAP2) to directly inhibit caspase-3, -7, and -9, but it otherwise upregulated the expression of mRNA and protein for DIABLO, an inhibitor of IAPs. Those adenosine effects were attenuated by dipyridamole. Caspase-3 and -8 were implicated in adenosine-induced HuH-7 cell death, and adenosine actually activated caspase-3 without caspase-9 activation. The caspase-3 activation was inhibited by overexpressing Bcl-X(L) or IAP2. Taken together, the results of the present study indicate that intracellularly transported adenosine activates caspase-3 by neutralizing caspase-3 inhibition due to IAP as a result of decreased IAP2 expression and reduced IAP activity in response to increased DIABLO expression and perhaps DIABLO release from damaged mitochondria, in addition to caspase-8 activation. This represents further insight into adenosine-induced HuH-7 cell apoptotic pathway.
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PMID:Adenosine-induced caspase-3 activation by tuning Bcl-XL/DIABLO/IAP expression in HuH-7 human hepatoma cells. 2006 52

Bortezomib (VELCADE) could sensitize certain human renal cell carcinoma (RCC) lines to the apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Analysis of seven human RCC showed a clear increase in the sensitivity of four of the RCC to TRAIL cytotoxicity following bortezomib (5-20 nmol/L) treatment, whereas the remaining three remained resistant. Tumor cell death following sensitization had all the features of apoptosis. The enhanced antitumor activity of the bortezomib and TRAIL combination was confirmed in long-term (6 days) cancer cell outgrowth assays. The extent of proteasome inhibition by bortezomib in the various RCC was equivalent. Following bortezomib treatment, neither changes in the intracellular protein levels of various Bcl-2 and IAP family members, nor minor changes in expression of TRAIL receptors (DR4, DR5), correlated well with the sensitization or resistance of RCC to TRAIL-mediated apoptosis. However, enhanced procaspase-8 activation following bortezomib pretreatment and subsequent TRAIL exposure was only observed in the sensitized RCC in both cell extracts and death-inducing signaling complex immunoprecipitates. These data suggest that the molecular basis for bortezomib sensitization of RCC to TRAIL primarily involves early amplification of caspase-8 activity. In the absence of this increased caspase-8 activation, other bortezomib-induced changes are not sufficient to sensitize RCC to TRAIL-mediated apoptosis.
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PMID:Bortezomib sensitizes human renal cell carcinomas to TRAIL apoptosis through increased activation of caspase-8 in the death-inducing signaling complex. 2044 97

Ganoderma lucidum, a well-known medicinal mushroom, is highly valued and commonly used in Oriental medicine. Although recent experimental data has revealed the proapoptotic potency of G. lucidum extracts, the underlying mechanisms of this apoptotic activity have not yet been studied in detail. In the present study, the effects of ethanol extracts of G. lucidum (EGL) on the growth of an AGS human gastric carcinoma cell line were investigated. We found that EGL treatment resulted in a dose and time-dependent significant decrease in the viability of AGS cells. This decreased viability was caused by apoptotic cell death, with observed chromatin condensation and an accumulation of apoptotic fraction. EGL treatment induced the expression of death receptor-related proteins such as death receptor 5 and tumor necrosis factor-related apoptosis-inducing ligand, which further triggered the activation of caspase-8 and the cleavage of Bid. In addition, the increase in apoptosis that was induced by EGL was correlated with activation of caspase-9 and -3, downregulation of IAP family proteins such as XIAP and survivin, and concomitant degradation of poly (ADP-ribose) polymerase. Moreover the activity of Akt was downregulated in EGL-treated cells, and the phosphatidylinositol-3 kinase/ Akt inhibitor LY294002 sensitized the cells to EGL-induced apoptosis. The results indicated that EGL induces the apoptosis of AGS cells through a signaling cascade of death receptor-mediated extrinsic, as well as mitochondria-mediated intrinsic, caspase pathways which are associated with inactivation of the Akt signal pathway.
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PMID:Induction of apoptosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. 2063 12

The pro-apoptotic activity of J-7, a synthetic methyl jasmonate derivative, on the Hep3B human hepatocarcinoma cell line was investigated. Treatment of Hep3B cells with J-7 resulted in growth inhibition and the induction of apoptosis as measured by trypan blue-excluding cells, MTT assay, nuclear staining, DNA fragmentation, and flow cytometry analysis. The increased apoptotic events in Hep3B cells caused by J-7 were associated with the alteration in the ratio of Bax/Bcl-2 protein expression. J-7 treatment induced the expression of death receptor-related proteins such as death receptor 5, which triggered the activation of caspase-8 and the down-regulation of the whole Bid expression. In addition, the apoptosis induction by J-7 was correlated with the activation of caspase-9 and caspase-3, down-regulation IAP family proteins such as XIAP and cIAP-1, and concomitant degradation of poly (ADP-ribose) polymerase. However, the cytotoxic and apoptotic effects induced by J-7 were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role that caspase-3 plays in the process. Furthermore, blocking the extracellular signal-regulated protein kinase and c-Jun N-terminal kinase pathways showed increased apoptosis and the activation of caspases in J-7-induced apoptosis. The results indicated that J-7 induces the apoptosis of Hep3B cells through a signaling cascade of death-receptor-mediated extrinsic as well as mitochondria-mediated intrinsic caspase pathways, which are associated with the activation of the mitogen-activated protein kinases signal pathway.
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PMID:A methyl jasmonate derivative, J-7, induces apoptosis in human hepatocarcinoma Hep3B cells in vitro. 2069 34


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