Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Present studies demonstrate that treatment with the histone deacetylases inhibitor LAQ824, a cinnamic acid hydroxamate, increased the acetylation of histones H3 and H4, as well as induced p21(WAF1) in the human T-cell acute leukemia Jurkat, B lymphoblast SKW 6.4, and acute myelogenous leukemia HL-60 cells. This was associated with increased accumulation of the cells in the G(1) phase of the cell cycle, as well as accompanied by the processing and activity of caspase-9 and -3, and apoptosis. Exposure to LAQ824 increased the mRNA and protein expressions of the death receptors DR5 and/or DR4, but reduced the mRNA and protein levels of cellular FLICE-inhibitory protein (c-FLIP). As compared with treatment with Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or LAQ824 alone, pretreatment with LAQ824 increased the assembly of Fas-associated death domain and caspase-8, but not of c-FLIP, into the Apo-2L/TRAIL-induced death-inducing signaling complex. This increased the processing of caspase-8 and Bcl-2 interacting domain (BID), augmented cytosolic accumulation of the prodeath molecules cytochrome-c, Smac and Omi, as well as led to increased activity of caspase-3 and apoptosis. Treatment with LAQ824 also down-regulated the levels of Bcl-2, Bcl-x(L), XIAP, and survivin. Partial inhibition of apoptosis due to LAQ824 or Apo-2L/TRAIL exerted by Bcl-2 overexpression was reversed by cotreatment with LAQ824 and Apo-2L/TRAIL. Significantly, cotreatment with LAQ824 increased Apo-2L/TRAIL-induced apoptosis of primary acute myelogenous leukemia blast samples isolated from 10 patients with acute myelogenous leukemia. Taken together, these findings indicate that LAQ824 may have promising activity in augmenting Apo-2L/TRAIL-induced death-inducing signaling complex and apoptosis of human acute leukemia cells.
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PMID:Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. 1505 15

Melanoma cells are relatively resistant to Apo2L/TRAIL (TNF-related apoptosis-inducing ligand). We postulated that resistance might result from higher expression of inhibitors of apoptosis including Bcl-2, FLIP (FLICE-like inhibitory protein) or IAPs such as XIAP (X-linked inhibitor of apoptosis) or survivin. Compared to scrambled or mismatch controls, targeting individual inhibitors with siRNA (si-Bcl-2, si-XIAP, si-FLIP or si-Surv), followed by Apo2L/TRAIL resulted in marked increase in apoptosis in melanoma cells. Compared to Bcl-2 or FLIP, siRNAs against XIAP and survivin were most potent in sensitizing melanoma cells. A similar substantial increase in apoptosis was seen in renal carcinoma cells (SKRC-45, Caki-2), following the inhibition of either XIAP or survivin by siRNAs. Apo2L/TRAIL treatment in IAP-targeted cells resulted in cleavage of Bid, activation of caspase-9 and cleavage of PARP (poly ADP-ribose polymerase). Thus, Apo2L/TRAIL resistance can be overcome by interfering with expression of inhibitors of apoptosis regulating both extrinsic (death receptor) or intrinsic (mitochondrial) pathways of apoptosis in melanoma cells.
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PMID:Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. 1511 63

Beta1-integrin protects keratinocyte stem cells (KSC) from cell-detachment apoptosis ('anoikis'). Here we show that caspase-8 active protein is detected in both young transit amplifying (TA) cells and TA cells, but not in KSC. On suspension, caspases are activated earlier in young TA than in KSC, whereas anti-beta1-integrin neutralizing antibody accelerates caspase activation in both KSC and young TA. Caspases 8 and 10 are the first caspases to be activated whereas caspase-8 inhibitor zIETD-fmk delays the activation of Bid, caspase-9 and caspase-3. However, the caspase-9 inhibitor zLEDH-fmk does not block the activation of caspase-8, Bid, caspase-10 and caspase-3. Moreover, caspase-8, but not caspase-9 inhibitor partially prevents keratinocyte anoikis. As FLIP inhibits caspase-8 processing, we retrovirally infected HaCaT keratinocytes with c-FLIP(L). Anti-beta1-integrin fails to activate caspase-8, Bid, caspase-9 and to induce the release of cytochrome c in c-FLIP(L) overexpressing keratinocytes. Finally, overexpression of c-FLIP(L) partially prevents anoikis in both suspended and anti-beta1 integrin-treated cells. Taken together, these results indicate that the extrinsic apoptotic pathway triggered by caspase-8 predominates in keratinocyte anoikis. However, the release of cytochrome c and the later activation of caspase-9 seem to suggest that the intrinsic mitochondrial pathway may intervene as a positive feedback loop of caspase activation.
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PMID:FLICE/caspase-8 activation triggers anoikis induced by beta1-integrin blockade in human keratinocytes. 1550 84

The balance between cell death and cell proliferation and its regulation are essential features of many physiological processes and are particularly important in fetal morphogenesis and adult tissue homeostasis. Apoptosis is a type of cell suicide that is activated in two main ways: through a receptor-mediated pathway or through a mitochondrial pathway. We have investigated the immunohistochemical distribution of proteins belonging to these two pathways in human placenta during gestation by comparing their expression levels between the first and third trimester of gestation. In the first trimester, the receptor-mediated pathway prevails over the mitochondrial pathway with a moderate/intense expression of its three components, viz., Fas ligand (FasL), Fas, and caspase-8, and weak positivity of anti-apoptotic FLIP, these proteins being mainly localized in the cytotrophoblast compartment. In the third trimester of gestation, there is an increased expression of mitochondrial pathway proteins, viz., Apaf-1 and caspase-9. We have also investigated the expression level of caspase-3, the primary effector caspase of both pathways, and have observed that it is moderately expressed during gestation, being mainly localized in the cytotrophoblast during the first trimester and in both placental compartments during the third trimester of gestation. Thus, both pathways actively function in human placenta to execute cell death. By means of immunoelectron microscopy, we have further shown that, in human placenta, the two proteins of the mitochondrial pathway together with caspase-3 are localized both in the cytoplasm and in the nucleus. In particular, Apaf-1 and caspase-9 are distributed near to the nuclear envelope suggesting an important role for these two proteins in disrupting the nuclear-cytoplasmic barrier.
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PMID:Immunohistochemical distribution of proteins belonging to the receptor-mediated and the mitochondrial apoptotic pathways in human placenta during gestation. 1557 74

Pancreatic cancer is characterised by a highly malignant phenotype with a marked resistance to conventional therapies and to apoptotic activators. Here, we demonstrate that sodium butyrate (NaBt), an inhibitor of histone deacetylases, sensitises human pancreatic cancer cell lines to both mitochondria- and Fas-mediated apoptosis. The analysis of anti-apoptotic and pro-apoptotic members of the Bcl-2 family in untreated pancreatic cancer cell lines shows a generalised low expression of Bcl-2 and a strong expression of Bcl-xL. NaBt treatment results in a marked down-regulation of Bcl-xL expression, mitochondrial membrane depolarization, cytochrome c release from mitochondria, activation of caspase-9 and -3 and apoptosis induction. Furthermore, NaBt sensitises pancreatic cancer cells to Fas-mediated apoptosis as well. In fact, the combined treatment with NaBt and the agonistic antibody anti-Fas (CH11) is able to induce apoptosis at an early time, in which neither NaBt nor CH11 alone induce apoptosis. Down-regulation of FLIP and activation of caspase-8 allow apoptosis to occur. These findings suggest that sodium butyrate could represent a good candidate for the development of new therapeutic strategies aimed at improving chemotherapy and immunotherapy in pancreatic cancer.
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PMID:Sodium butyrate sensitises human pancreatic cancer cells to both the intrinsic and the extrinsic apoptotic pathways. 1610 47

Promyelocytic leukemia HL-60 cells are resistant to Fas-mediated apoptosis. The signaling pathway for Fas-mediated apoptosis in various cells, including HL-60 cells, is currently unknown. Here, we studied the role of survival/apoptosis associated phosphatidylinositol 3-kinase (PI 3-K)/Akt in this process. We found that both PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed phosphorylation of Akt and Bad in HL-60 cells. PI 3-K inhibitors significantly accelerated not only spontaneous apoptosis, but also Fas-induced apoptosis in HL-60 cells. The pro-apoptotic effect of PI 3-K inhibitors favored Fas-mediated apoptosis rather than spontaneous apoptosis in HL-60 cells. The caspase-3 or -8 inhibitor reduced the pro-apoptotic effect of the PI 3-K inhibitors for Fas-mediated apoptosis in HL-60 cells, but the caspase-9 inhibitor did not. Although PI 3-K inhibitors did not affect Fas expression in HL-60 cells, cellular FLICE-inhibitory protein (c-FLIP) levels were markedly reduced by PI 3-K inhibitor treatment. Furthermore, antisense oligonucleotide of c-FLIP confirmed that down-regulation of c-FLIP enhanced sensitization to Fas-mediated apoptosis in HL-60 cells. These results suggest that the PI 3-K/Akt signaling pathway may, in part, regulate Fas-mediated apoptosis in HL-60 cells through c-FLIP expression.
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PMID:Enhancement of susceptibility to Fas-mediated apoptosis in HL-60 cells through down-regulation of cellular FLICE-inhibitory protein by phosphatidylinositol 3-kinase inhibitors. 1621 Dec 88

Transforming growth factor beta (TGF-beta) has been implicated in the maintenance of homeostasis in various organs, including the gastric epithelium. In particular, TGF-beta-induced signaling was shown to be required for the differentiation-associated physiological apoptosis of gastric epithelial cells, but its mechanism has not been well understood. In this study, the molecular mechanism of TGF-beta-induced apoptosis was analyzed in a human gastric epithelial cell line, SNU16, as an in vitro model. Expression of Smad7 and Bcl-X(L), but not viral FLIP, was shown to prevent TGF-beta-induced apoptosis, indicating an exclusive requirement of the activation of Smad signaling pathway and mitochondrial dysfunction followed by activation of caspase-9. In addition, treatment with TGF-beta induced binding of Bim, a proapoptotic Bcl-2 homology domain 3 (BH3)-only protein, to Bcl-X(L), which is dependent on the activation of Smad, and reduction in the expression of Bim by RNA interference decreased the sensitivity to TGF-beta-induced apoptosis. Moreover, we found abnormalities in the gastric epithelium of both Bim and caspase-9 knockout mice; these abnormalities were associated with a defect of physiological apoptosis in gastric epithelial cells. These results indicate for the first time that TGF-beta is involved in the physiological loss of gastric epithelial cells by activating apoptosis mediated by Smad, Bim, and caspase-9.
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PMID:Transforming growth factor beta-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. 1626 Jun 15

Death receptor signaling is initiated by the assembly of the death-inducing signaling complex, which culminates in the activation of the initiator caspase, either caspase-8 or caspase-10. A family of viral and cellular proteins, known as FLIP, plays an essential role in the regulation of death receptor signaling. Viral FLIP (v-FLIP) and short cellular FLIP (c-FLIPS) inhibit apoptosis by interfering with death receptor signaling. The structure and mechanisms of v-FLIP and c-FLIPS remain largely unknown. Here we report a high resolution crystal structure of MC159, a v-FLIP derived from the molluscum contagiosum virus, which is a member of the human poxvirus family. Unexpectedly, the two tandem death effector domains (DEDs) of MC159 rigidly associate with each other through a hydrophobic interface. Structure-based sequence analysis suggests that this interface is conserved in the tandem DEDs from other v-FLIP, c-FLIPS, and caspase-8 and -10. Strikingly, the overall packing arrangement between the two DEDs of MC159 resembles that between the caspase recruitment domains of Apaf-1 and caspase-9. In addition, each DED of MC159 contains a highly conserved binding motif on the surface, to which loss-of-function mutations in MC159 map. These observations, in conjunction with published evidence, reveal significant insights into the function of v-FLIP and suggest a mechanism by which v-FLIP and c-FLIPS inhibit death receptor signaling.
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PMID:Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition of death receptor signaling. 1631

In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to Fas-mediated apoptosis during in vitro culture. Here, we studied the role of survival/apoptosis associated phosphatidylinositol 3-kinase (PI 3-K)/Akt in this process. We found that both PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed the phosphorylation of Akt and accelerated Fas-mediated apoptosis in OSCC cells. It was found that caspase-3 and -8 inhibitors reduced the accelerative effect of PI 3-K inhibitor on Fas-mediated apoptosis in OSCC cells, but not caspase-9 inhibitor. Although PI 3-K inhibitors did not affect the Fas expression of OSCC cells, cellular FLICE-inhibitory protein (c-FLIP) levels were markedly reduced by PI 3-K inhibitor treatment. Moreover, antisense oligonucleotide to c-FLIP confirmed that the down-regulation of c-FLIP enhanced the sensitization to Fas-mediated apoptosis in OSCC cells. These results suggest that PI 3-K/Akt signaling pathway may, in part, regulate Fas-mediated apoptosis in OSCC cells through c-FLIP expression.
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PMID:Enhancement of susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells by phosphatidylinositol 3-kinase inhibitor. 1652 14

Human endometrial epithelial cells undergo apoptosis immediately before the menstrual period. Apoptotic signalling was analysed using human endometrial tissue and a human endometrial carcinoma cell line (HHUA). Activity levels of caspase-3, -8, and -9 were elevated in human endometrium during the late secretory phase and in HHUA cells incubated with an anti-Fas monoclonal antibody (mAb). Fas-mediated apoptosis of HHUA cells was blocked by prior exposure to inhibitors of caspase-9, -8 and -3. In HHUA cells treated with anti-Fas mAb, a release of cytochrome c was detected in the cytosolic fraction, in addition a full-length Bid was degraded. Full-length FLIP(L) (p55) was degraded during apoptosis, and p29 (regarded as the product of p55 cleavage) appeared instead of FLIP(L). In normal human endometrial tissue, Bid degradation was also observed in a cyclic manner with a peak during the early secretory phase of the menstrual cycle. Furthermore, the release of cytochrome c was seen in the early secretory phase. However, expression of FLIP(S) was only observed during the menstrual cycle in normal endometrial tissue. We concluded that the main apoptotic signalling in both normal human endometrial tissue and HHUA cells exposed to anti-Fas mAb is the mitochondrial pathway via Bid degradation. Although the function of FLIP is still unknown on normal endometrial tissue, it may be regulated by FLIP(L) expression on HHUA cells derived from human endometrial carcinoma.
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PMID:Caspase cascade of Fas-mediated apoptosis in human normal endometrium and endometrial carcinoma cells. 1687 Sep 53


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