scholarly journals Selective Knockdown of the Long Variant of Cellular FLICE Inhibitory Protein Augments Death Receptor-mediated Caspase-8 Activation and Apoptosis

2005 ◽  
Vol 280 (19) ◽  
pp. 19401-19409 ◽  
Author(s):  
Darcie A. Sharp ◽  
David A. Lawrence ◽  
Avi Ashkenazi
Keyword(s):  
Death Receptor ◽  
Caspase 8 ◽  
Inhibitory Protein

scholarly journals Caspase-8 prevents sustained activation of NF-κB in monocytes undergoing macrophagic differentiation

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1442-1450 ◽  
Author(s):  
Cédric Rébé ◽  
Séverine Cathelin ◽  
Sophie Launay ◽  
Rodolphe Filomenko ◽  
Laurent Prévotat ◽  
...  
Keyword(s):  
Death Receptor ◽  
Adaptor Protein ◽  
Cell Types ◽  
Caspase 8 ◽  
Specific Cell ◽  
Death Domain ◽  
Blood Monocytes ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
Macrophage Colony

Abstract Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-κB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-κB activity through RIP1 cleavage.

scholarly journals C5, A Cassaine Diterpenoid Amine, Induces Apoptosis via the Extrinsic Pathways in Human Lung Cancer Cells and Human Lymphoma Cells

2020 ◽  
Vol 21 (4) ◽  
pp. 1298 ◽  
Author(s):  
Hyo-Jin Kim ◽  
Bo-Gyeong Seo ◽  
Kwang Dong Kim ◽  
Jiyun Yoo ◽  
Joon-Hee Lee ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Death Receptor ◽  
B Cell Lymphoma ◽  
Human Lung Cancer ◽  
Caspase 8 ◽  
Death Domain ◽  
Extrinsic Pathway ◽  
Inhibitory Protein ◽  
Apoptosis Pathways ◽  
Induced Apoptosis

Apoptosis pathways in cells are classified into two pathways: the extrinsic pathway, mediated by binding of the ligand to a death receptor and the intrinsic pathway, mediated by mitochondria. Apoptosis is regulated by various proteins such as Bcl-2 (B-cell lymphoma 2) family and cellular FLICE (Fas-associated Death Domain Protein Interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which have been reported to inhibit caspase-8 activity. In this study, it was found that C5 (3β-Acetyl-nor-erythrophlamide), a compound of cassaine diterpene amine from Erythrophleum fordii, induced cell apoptosis in a variety of types of cancer cells. Induction of apoptosis in cancer cells by C5 was inversely related to the level of Bcl-2 expression. Overexpression of Bcl-2 into cancer cells significantly decreased C5-induced apoptosis. It was also found that treatment of cancer cells with a caspase-8 inhibitor significantly suppressed C5-induced apoptosis; however, treatment with caspase-9 inhibitors did not affect C5-induced apoptosis, suggesting that C5 may induce apoptosis via the extrinsic pathway by activating caspase-8. It was confirmed that treatment with C5 alone induced an association of FADD with procaspase-8; however, overexpression of c-FLIP decreased C5-induced caspase-8 activation. In conclusion, C5 could be utilized as a new useful lead compound for the development of an anti-cancer agent that has the goal of apoptosis.

scholarly journals Hypo-Expression of Flice-Inhibitory Protein and Activation of the Caspase-8 Apoptotic Pathways in the Death-Inducing Signaling Complex Due to Ischemia Induced by the Compression of the Asphyxiogenic Tool on the Skin in Hanging Cases

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 938
Author(s):  
Aniello Maiese ◽  
Alessandra De Matteis ◽  
Giorgio Bolino ◽  
Emanuela Turillazzi ◽  
Paola Frati ◽  
...  
Keyword(s):  
Tertiary Structure ◽  
Active Form ◽  
Three Dimensional ◽  
Death Receptor ◽  
Cell Receptor ◽  
Control Group ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Signaling Complex ◽  
Induced Apoptosis

The FLICE-inhibitory protein (c-FLIPL) (55 kDa) is expressed in numerous tissues and most abundantly in the kidney, skeletal muscles and heart. The c-FLIPL has a region of homology with caspase-8 at the carboxy-terminal end which allows the molecule to assume a tertiary structure similar to that of caspases-8 and -10. Consequently, c-FLIPL acts as a negative inhibitor of caspase-8, preventing the processing and subsequent release of the pro-apoptotic molecule active form. The c-FLIP plays as an inhibitor of apoptosis induced by a variety of agents, such as tumor necrosis factor (TNF), T cell receptor (TCR), TNF-related apoptosis inducing ligand (TRAIL), Fas and death receptor (DR). Increased expression of c-FLIP has been found in many human malignancies and shown to be involved in resistance to CD95/Fas and TRAIL receptor-induced apoptosis. We wanted to verify an investigative protocol using FLIP to make a differential diagnosis between skin sulcus with vitality or non-vital skin sulcus in hanged subjects and those undergoing simulated hanging (suspension of the victim after murder). The study group consisted of 21 cases who died from suicidal hanging. The control group consisted of traumatic or natural deaths, while a third group consisted of simulated hanging cases. The reactions to the Anti-FLIP Antibody (Abcam clone-8421) was scored for each section with a semi-quantitative method by means of microscopic observation carried out with confocal microscopy and three-dimensional reconstruction. The results obtained allow us to state that the skin reaction to the FLIP is extremely clear and precise, allowing a diagnosis of unequivocal vitality and a very objective differentiation with the post-mortal skin sulcus.

scholarly journals Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma

2018 ◽  
Vol 19 (12) ◽  
pp. 3798 ◽  
Author(s):  
Giulia Fianco ◽  
Claudia Contadini ◽  
Alessandra Ferri ◽  
Claudia Cirotti ◽  
Venturina Stagni ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Cellular Systems ◽  
Caspase 8 ◽  
Cancer Resistance ◽  
Inhibitory Protein ◽  
Novel Target

Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.

scholarly journals Programmed Cell Death of Embryonic Motoneurons Triggered through the FAS Death Receptor

1999 ◽  
Vol 147 (5) ◽  
pp. 1049-1062 ◽  
Author(s):  
Cédric Raoul ◽  
Christopher E. Henderson ◽  
Brigitte Pettmann
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Neurotrophic Factors ◽  
Caspase 3 ◽  
Death Receptor ◽  
Trophic Factors ◽  
Caspase 8 ◽  
Spinal Motoneurons ◽  
Inhibitory Protein ◽  
Soluble Fasl

About 50% of spinal motoneurons undergo programmed cell death (PCD) after target contact, but little is known about how this process is initiated. Embryonic motoneurons coexpress the death receptor Fas and its ligand FasL at the stage at which PCD is about to begin. In the absence of trophic factors, many motoneurons die in culture within 2 d. Most (75%) of these were saved by Fas-Fc receptor body, which blocks interactions between Fas and FasL, or by the caspase-8 inhibitor tetrapeptide IETD. Therefore, activation of Fas by endogenous FasL underlies cell death induced by trophic deprivation. In the presence of neurotrophic factors, exogenous Fas activators such as soluble FasL or anti-Fas antibodies triggered PCD of 40–50% of purified motoneurons over the following 3–5 d; this treatment led to activation of caspase-3, and was blocked by IETD. Sensitivity to Fas activation is regulated: motoneurons cultured for 3 d with neurotrophic factors became completely resistant. Levels of Fas expressed by motoneurons varied little, but FasL was upregulated in the absence of neurotrophic factors. Motoneurons resistant to Fas activation expressed high levels of FLICE-inhibitory protein (FLIP), an endogenous inhibitor of caspase-8 activation. Our results suggest that Fas can act as a driving force for motoneuron PCD, and raise the possibility that active triggering of PCD may contribute to motoneuron loss during normal development and/or in pathological situations.

scholarly journals Viral FLIP Enhances Wnt Signaling Downstream of Stabilized β-Catenin, Leading to Control of Cell Growth

2005 ◽  
Vol 25 (21) ◽  
pp. 9249-9258 ◽  
Author(s):  
Shiho Nakagiri ◽  
Akira Murakami ◽  
Shinji Takada ◽  
Tetsu Akiyama ◽  
Shin Yonehara
Keyword(s):  
Wnt Signaling ◽  
Cell Lines ◽  
Death Receptor ◽  
Binding Activity ◽  
Luciferase Assay ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Direct Binding ◽  
Death Effector ◽  
Transformed Cell Lines

ABSTRACT Death receptor-mediated apoptosis is potently inhibited by viral FLIP (FLICE/caspase 8 inhibitory protein), which is composed of two tandemly repeated death effector domains (DEDs), through reduced activation of procaspase 8. Here, we show that equine herpesvirus 2-encoded viral FLIP E8 enhances Wnt/β-catenin signaling in a variety of cell lines. E8 was shown to strikingly augment Wnt3a signaling, as shown both in a luciferase assay for T-cell factor/β-catenin and through induction of endogenous cyclin D1. The effect of E8 was independent of its direct binding activity with DED-containing signaling molecules, including caspase 8 and FADD, in death receptor-mediated apoptosis. E8 enhanced Wnt signaling downstream of stabilized β-catenin, while a long form of cellular FLIP (c-FLIPL) enhanced stabilization of β-catenin in 293T cells. Consequently, coexpression of E8 and c-FLIPL synergistically increased Wnt signaling in 293T cells. Moreover, E8-mediated stimulation of Wnt signaling induced dramatic growth retardation in untransformed cell lines but not in transformed cell lines. Thus, viral FLIP E8 not only inhibits death receptor-mediated apoptosis but also enhances Wnt signaling pathways that are closely related to those of both ontogenesis and oncogenesis.

scholarly journals Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer

Oncogene ◽  
2001 ◽  
Vol 20 (41) ◽  
pp. 5865-5877 ◽  
Author(s):  
Simone Fulda ◽  
Martin U Küfer ◽  
Eric Meyer ◽  
Frans van Valen ◽  
Barbara Dockhorn-Dworniczak ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Death Receptor ◽  
Caspase 8 ◽  
Drug Induced ◽  
Or Gene ◽  
Induced Apoptosis

scholarly journals Caspase-8 deficiency induces a switch from TLR3 induced apoptosis to lysosomal cell death in neuroblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Anaïs Locquet ◽  
Gabriel Ichim ◽  
Joseph Bisaccia ◽  
Aurelie Dutour ◽  
Serge Lebecque ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Neuroblastoma Cell ◽  
Death Receptor ◽  
Neuroblastoma Cell Line ◽  
Caspase 8 ◽  
Caspase Activation ◽  
Extrinsic Pathway ◽  
Lysosomal Membrane Permeabilization ◽  
Induced Apoptosis

AbstractIn cancer cells only, TLR3 acquires death receptor properties by efficiently triggering the extrinsic pathway of apoptosis with Caspase-8 as apical protease. Here, we demonstrate that in the absence of Caspase-8, activation of TLR3 can trigger a form of programmed cell death, which is distinct from classical apoptosis. When TLR3 was activated in the Caspase-8 negative neuroblastoma cell line SH-SY5Y, cell death was accompanied by lysosomal permeabilization. Despite caspases being activated, lysosomal permeabilization as well as cell death were not affected by blocking caspase-activity, positioning lysosomal membrane permeabilization (LMP) upstream of caspase activation. Taken together, our data suggest that LMP with its deadly consequences represents a “default” death mechanism in cancer cells, when Caspase-8 is absent and apoptosis cannot be induced.

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