EC:3.4.22.61 - FACTA Search

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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)

Members of the tumor necrosis factor (TNF) receptor (TNFR) superfamily are potent regulators of apoptosis, a process that is important for the maintenance of immune homeostasis. Recent evidence suggests that TNFR-1 and Fas and TRAIL receptors can also trigger an alternative form of cell death that is morphologically distinct from apoptosis. Because distinct molecular components including the serine/threonine protein kinase receptor-interacting protein (RIP) are required, we have referred to this alternative form of cell death as "programmed necrosis." We show that TNFR-2 signaling can potentiate programmed necrosis via TNFR-1. When cells were pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, enhanced cell death and recruitment of RIP to the TNFR-1 complex were observed. However, TNF-induced programmed necrosis was normally inhibited by caspase-8 cleavage of RIP. To ascertain the physiological significance of RIP and programmed necrosis, we infected Jurkat cells with vaccinia virus (VV) and found that VV-infected cells underwent programmed necrosis in response to TNF, but deficiency of RIP rescued the infected cells from TNF-induced cytotoxicity. Moreover, TNFR-2-/- mice exhibited reduced inflammation in the liver and defective viral clearance during VV infection. Interestingly, death effector domain-containing proteins such as MC159, E8, K13, and cellular FLIP, but not the apoptosis inhibitors Bcl-xL, p35, and XIAP, potently suppressed programmed necrosis. Thus, TNF-induced programmed necrosis is facilitated by TNFR-2 signaling and caspase inhibition and may play a role in controlling viral infection.
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PMID:A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses. 1453 86

TRAIL appears to be a promising anticancer agent in that it induces apoptosis in a wide range of cancer cells but not normal tissues. Sensitivity of melanoma cells to TRAIL-induced apoptosis varied considerably because of their development of various resistance mechanisms against apoptosis. We discuss in this report the potential effect of a histone deacetylase inhibitor SBHA on TRAIL-induced apoptosis. Histone deacetylase (HDAC) inhibitors regulate histone acetylation and thereby modulate the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation, and apoptosis. Suberic bishydroxamate (SBHA) is a relatively new HDAC inhibitor that induced apoptosis in the majority of melanoma cell lines through a mitochondrial and caspase-dependent pathway. This was due to its regulation of the expression of multiple proteins that are involved in either the mitochondrial apoptotic pathway (Bcl-2 family members) or the final phase of apoptosis (caspase-3 and XIAP). Co-treatment with SBHA at nontoxic doses and TRAIL resulted in a marked increase in TRAIL-induced apoptosis of melanoma, but showed no toxicity to melanocytes. SBHA appeared to sensitize melanoma to TRAIL-induced apoptosis by up-regulation of pro-apoptotic proteins in the TRAIL-induced apoptotic pathway such as caspase-8, caspase-3, Bid, Bak, and Bax, and up-regulation of the BH3 domain only protein, Bim. This, together with activated Bid, may have acted synergistically to cause changes in mitochondria. Treatment with SBHA also resulted in down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-X(L) and Mcl-1, and the IAP member, XIAP. These changes would further facilitate apoptotic signaling. SBHA appeared therefore to be a potent agent in overcoming resistance of melanoma to TRAIL-induced apoptosis.
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PMID:The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. 1455 32

Interactions between proteasome and cyclin-dependent kinase inhibitors have been examined in human leukemia cells in relation to induction of apoptosis. Simultaneous exposure (24 h) of U937 myelomonocytic leukemia cells to 100 nM flavopiridol and 300 nM MG-132 resulted in a marked increase in mitochondrial injury (cytochrome c, Smac/DIABLO release, loss of deltaPsi(m)), caspase activation, and synergistic induction of cell death, accompanied by a marked decrease in clonogenic potential. Similar effects were observed with other proteasome inhibitors (e.g., Bortezomib (VELCADE trade mark bortezomib or injection), lactacystin, LLnL) and cyclin-dependent kinase inhibitors (e.g., roscovitine), as well as other leukemia cell types (e.g., HL-60, Jurkat, Raji). In U937 cells, synergistic interactions between MG-132 and flavopiridol were associated with multiple perturbations in expression/activation of signaling- and survival-related proteins, including downregulation of XIAP and Mcl-1, activation of JNK and p34(cdc2), and diminished expression of p21(CIP1). The lethal effects of MG-132/flavopiridol were not reduced in leukemic cells ectopically expressing Bcl-2, but were partially attenuated in cells ectopically expressing dominant-negative caspase-8 or CrmA. Flavopiridol/proteasome inhibitor-mediated lethality was also significantly diminished by agents and siRNA blocking JNK activation. Lastly, coadministration of MG-132 with flavopiridol resulted in diminished DNA binding of NF-kappaB. Notably, pharmacologic interruption of the NF-kappaB pathway (e.g., by BAY 11-7082, PDTC, or SN-50) or molecular dysregulation of NF-kappaB (i.e., in cells ectopically expressing an IkappaBalpha super-repressor) mimicked the actions of proteasome inhibitors in promoting flavopiridol-induced mitochondrial injury, JNK activation, and apoptosis. Together, these findings indicate that proteasome inhibitors strikingly lower the apoptotic threshold of leukemic cells exposed to pharmacologic CDK inhibitors, and suggest that interruption of the NF-kappaB cytoprotective pathway and JNK activation both play key roles in this phenomenon. They also raise the possibility that combining proteasome and CDK inhibitors could represent a novel antileukemic strategy.
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PMID:Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. 1456 39

It is well known that dysfunction of the apoptotic pathway confers apoptosis resistance and results in a low sensitivity of human cancer cells to therapeutic agents. A novel strategy to overcome the resistance is to target the apoptotic pathway directly. To identify molecular targets in the apoptotic pathway that are differentially regulated in cancer and normal cells, we have examined the levels of apoptotic effectors and inhibitors in human tumor and normal cell lines as well as in cancer and normal tissues. These include three pancreatic cancer lines (BXPC-3, MIA PaCa-2, and Panc-1), four breast cancer cell lines (MDA-MB-231, MDA-MB-435, MDA-MB-361, and MCF-7), and colon carcinoma line (SW620). Additionally, breast carcinoma tissue specimens were examined. Compared with normal human fibroblast and mammary epithelial cell lines, we detected high basal levels of caspase-3 and caspase-8 activities and active caspase-3 fragments in the tumor cell lines and cancer tissues in the absence of apoptotic stimuli. Furthermore, the tumor cells expressed high levels of survivin and XIAP, two members of the inhibitor of apoptosis (IAP) protein family. When the activity of these IAPs was blocked by expression of dominant-negative mutant survivin (survivinT34A) and XIAP-associated factor 1, respectively, apoptosis was induced in tumor but not normal cell lines. Moreover, down-regulation of both survivin and XIAP significantly enhanced tumor-cell apoptosis as compared with inhibition of either survivin or XIAP alone. These results suggest that up-regulated IAP expression counteracts the high basal caspase-3 activity observed in these tumor cells and that apoptosis in tumor cells but not normal cells can be induced by blocking IAP activity. Therefore, IAPs are important molecular targets for the development of cancer-specific therapeutic approaches.
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PMID:Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. 1458 79

PPARgamma is known to induce apoptosis in malignant tumor cells, but the mechanism of this induction is not well understood. We investigated induction of apoptosis with 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a PPARgamma ligand, in cholangio cell carcinoma (CCC) cells (RBE, ETK-1 or HuCCT-1). Apoptosis was induced in RBE and ETK-1 cells with 15d-PGJ2, but not in HuCCT-1 cells, although PPARgamma was expressed in all CCC cells. Apoptosis-related proteins were also expressed, including FLIP, bclx, Apaf-1 and XIAP, but expression levels differed among the three cell lines. RBE cells treated with 15d-PGJ2 showed caspase activation, and it appeared that PPARgamma-induced apoptosis was dependent on caspase activation. However, neither ETK-1 nor HuCCT-1 cells showed significant activation of caspase-8 or -3 with 15d-PGJ2 treatment, raising the possibility of a caspase-independent apoptosis induction pathway. XIAP was down-regulated by 15d-PGJ2 in all three CCC cell lines. Therefore, 15d-PGJ2 induces apoptosis in CCC cells via caspase-dependent or independent pathways. 15d-PGJ2 may also induce down-regulation of XIAP and may promote caspase cascade activation through TNF-family receptor signaling pathways.
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PMID:The PPARgamma ligand, 15-Deoxy-Delta12,14-PGJ2, regulates apoptosis-related protein expression in cholangio cell carcinoma cells. 1461 59

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells. We investigated TRAIL sensitivity and the TRAIL-induced apoptosis signalling pathway in a panel of B-lymphocytic leukaemia cell lines. Depending upon TRAIL sensitivity, leukaemia cells could be divided into three groups: highly sensitive, moderately sensitive and resistant. TRAIL receptor-2 (DR5) plays an important role in transducing apoptosis signals. DR5 was internalized into the cytoplasm where it recruited FAS-associated death domain protein (FADD) under TRAIL stimulation in both sensitive and resistant cells. However, the active form of caspase-8 was recruited to FADD and only sensitive cells showed increased caspase-8 activity upon TRAIL stimulation. The caspase-8 specific inhibitor, Z-IETD, impaired caspase-8 activation and completely abrogated TRAIL-induced apoptosis. These results suggest that TRAIL resistance in B-lymphocytic leukaemia cells is due to negative regulation at the level of caspase-8 activation and that caspase-8 activation is an indispensable process in TRAIL-induced apoptosis. However, FADD-like interleukin-1 beta-converting enzyme inhibitory protein (c-FLIPL) was similarly expressed and down-regulated after TRAIL stimulation in both sensitive and resistant cells. Interestingly, in some cell lines, TRAIL sensitivity and caspase-8 activity was enhanced or restored with the treatment of cycloheximide (CHX). In addition, X-linked inhibitor of apoptosis (XIAP) levels decreased significantly and rapidly following treatment with CHX. Down-regulation of XIAP may be responsible for enhancement or restoration of TRAIL sensitivity after CHX treatment in B-lymphocytic leukaemia cells.
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PMID:Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines. 1463 85

Apoptosis occurs in the placenta throughout gestation, with a greater frequency near term in comparison to the first trimester. The Fas/FasL system represents one of the main apoptotic pathways controlling placental apoptosis. Although first trimester trophoblast cells express both Fas and FasL, they are resistant to Fas-induced apoptosis. Therefore, trophoblast resistance to Fas-mediated apoptosis may be due to the inhibition of the pathway downstream of Fas stimulation. Expression levels of X-linked inhibitor of apoptosis (XIAP) were recently shown to decrease in third trimester placentas, correlating with an increase in placental apoptosis. As a potent caspase inhibitor, XIAP prevents the activation of caspase-9 through its BIR3 domain and caspase-3 activation via the linker-BIR2 domain. In the present study, high levels of the active form of XIAP were detected in first trimester trophoblast cells, whereas term placental tissue samples predominantly expressed the inactive form of XIAP. Using a XIAP inhibitor, phenoxodiol, we demonstrate that XIAP inactivation sensitizes trophoblast cells to Fas stimulation, as evidenced by the anti-Fas mAb-induced decrease in trophoblast cell viability and increase in caspase-8, caspase-9 and caspase-3 activation. This suggests a functional role for XIAP in the regulation of the Fas apoptotic cascade in trophoblast cells during pregnancy.
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PMID:X-linked inhibitor of apoptosis (XIAP) confers human trophoblast cell resistance to Fas-mediated apoptosis. 1466 4

Interactions between histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand, were examined in human leukemia cells (e.g., U937, Jurkat, and HL-60). Simultaneous exposure of cells to 100-ng/ml TRAIL with either 1-mM sodium butyrate or 2- micro M suberoylanilide hydroxamic acid resulted in a striking increase in leukemic cell mitochondrial damage, caspase activation, and apoptosis. Lethal effects were significantly diminished in U937 cells ectopically expressing dominant-negative caspase-8, dominant-negative Fas-associated death domain, CrmA (receptor pathway), or Bcl-2 or Bcl-X(L) (mitochondrial pathway). Analysis of mitochondrial events in U937 cells exposed to TRAIL/HDAC inhibitors revealed enhanced Bid activation and Bax translocation, loss of mitochondrial membrane potential, and cytoplasmic release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor. No changes were observed in expression of FLICE-like inhibitory protein, TRAIL receptors, or reactive oxygen species generation. TRAIL/HDAC inhibitor-induced apoptosis triggered caspase-dependent cleavage of p21(WAF1/CIP1); moreover, enforced expression of a nuclear localization signal deletant form of p21(WAF1/CIP1) significantly diminished lethality. Lastly, p27(KIP1), pRb, X-linked inhibitor of apoptosis, and Bcl-2 displayed extensive proteolysis. These findings indicate that coadministration of TRAIL with HDAC inhibitors synergistically induces apoptosis in human myeloid leukemia cells and provide further evidence that simultaneous activation of the extrinsic and intrinsic pathways in such cells leads to a dramatic increase in mitochondrial injury and activation of the caspase cascade.
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PMID:Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. 1470 68

There are many factors contributing to the resistance to TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. However, it is not clear whether the mechanism of resistance to TRAIL is constitutive or inductive. Therefore, the purpose of this study was to investigate the resistant mechanisms to TRAIL at different levels in the apoptotic pathway. The human T-lymphoblastic leukemic CEM cell line showed more resistant to TRAIL-induced apoptosis compared with the human chronic myeloid leukemic K562 cell line. Lower level of constitutive caspase-8 expression in the CEM cell line led to a poor response to both TRAIL-induced activation of caspase-3 and reduction in the mitochondrial membrane potential (DeltaPsim). There was no significant difference in the constitutive levels of NF-kappaB in CEM and K562 cell lines. However, CEM cells showed a faster response to TRAIL-induced NF-kappaB activation than K562 cells. TRAIL-induced regulation of Bcl-2 family of proteins included an up-regulation in Bcl-2/Bcl-XL and a down-regulation in Bax. IAPs, such as XIAP, cIAP-1, cIAP-2 and Survivin were all up-regulated during the treatment with TRAIL. In summary, our data suggest that the leukemic cells resistance to TRAIL-induced apoptosis might be due to the deficiency in the constitutive caspase-8 expression. Development of potential resistance to apoptosis by TRAIL can occur in both TRAIL-resistant and TRAIL-sensitive leukemic cells.
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PMID:Potential mechanisms of leukemia cell resistance to TRAIL-induced apopotosis. 1473 5

Over the last decade, a great deal of attention has been directed at elucidating the role of apoptosis regulators in governing survival decisions in neoplastic cells, particularly those of hematopoietic origin. A major focus of this work has involved investigation of the function of pro- and anti-apoptotic members of the BCL-2 family, and the relationship between these proteins and mitochondrial integrity. Currently, these proteins can be classified into two broad categories: those that modulate mitochondrial function and those that regulate the activation of caspases responsible for activation and execution of the apoptotic cascade. Within the first category, certain proteins (e.g., BCL-2, BCL-xL) act to preserve mitochondrial integrity by preventing loss of mitochondrial membrane potential and/or release of pro-apoptotic proteins such as cytochrome C into the cytosol. Other proapoptotic proteins (e.g., BAX, BAK, BIM) promote release of cytochrome C. These proteins are therefore primarily involved in regulation of the intrinsic, mitochondrial apoptotic pathway. Within the second category, proteins such as the inhibitors of apoptosis proteins (e.g., XIAP) or FLIP block the activation of caspases, particularly those involved in engagement of the receptor-related, extrinsic apoptotic pathway. Cross-talk between the intrinsic and extrinsic pathways exists. For example, the BH3-domain only protein BID is cleaved by the activation of pro-caspase-8 through the extrinsic pathway, and translocates to the mitochondrion to promote cytochrome C release. Apoptosis is also regulated by various signal transduction pathways, possibly through post-translational modifications in BCL-2 family proteins. For example, phosphorylation of BCL-2 through a JNK-dependent mechanism has been postulated to contribute to apoptosis induced by the taxane class of cytotoxic agents. Finally, attempts to modulate apoptotic pathways with small molecules have recently received much attention. For example, small molecule inhibitors of BCL-2 or mimetics of SMAC/DIABLO, which opposes the actions of XIAP, have recently been shown to promote the antineoplastic activity of conventional cytotoxic agents. It is likely that an improved understanding of apoptosis regulation will lead to new insights into neoplastic transformation, and may also provide important leads for the development of novel antileukemic strategies.
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PMID:Apoptosis regulators. 1476 59

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