The Death Receptor Family and the Extrinsic Pathway

2003 ◽  
pp. 67-84
Author(s):  
Maria Eugenia Guicciardi ◽  
Gregory J. Gores
Keyword(s):  
Death Receptor ◽  
Extrinsic Pathway ◽  
Receptor Family

The Death Receptor Family and the Extrinsic Pathway

2003 ◽  
pp. 67-84
Author(s):  
Maria Eugenia Guicciardi ◽  
Gregory J. Gores
Keyword(s):  
Death Receptor ◽  
Extrinsic Pathway ◽  
Receptor Family

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.

scholarly journals The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis

2020 ◽  
Author(s):  
Lu Li ◽  
An Tong ◽  
Qiangsheng Zhang ◽  
Yuquan Wei ◽  
Xiawei Wei
Keyword(s):  
Molecular Mechanisms ◽  
Death Receptor ◽  
Kinase Domain ◽  
External Stress ◽  
Programmed Necrosis ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Caspase Inhibition ◽  
Regulated Necrosis ◽  
Receptor Family

Abstract Necrosis, a type of unwanted and passive cell demise, usually occurs under the excessive external stress and is considered to be unregulated. However, under some special conditions such as caspase inhibition, necrosis is regulable in a well-orchestrated way. The term ‘regulated necrosis’ has been proposed to describe such programmed necrosis. Recently, several forms of necrosis, including necroptosis, pyroptosis, ferroptosis, parthanatos, oxytosis, NETosis, and Na+/K+-ATPase-mediated necrosis, have been identified, and some crucial regulators governing regulated necrosis have also been discovered. Mixed lineage kinase domain-like pseudokinase (MLKL), a core regulator in necroptosis, acts as an executioner in response to ligands of death receptor family. Its activation requires the receptor-interacting protein kinases, RIP1 and RIP3. However, MLKL is only involved in necroptosis, that is, MLKL is dispensable for necrosis. Therefore, this review is aimed at summarizing the molecular mechanisms of MLKL-dependent and MLKL-independent necrosis.

scholarly journals Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models

2019 ◽  
Vol 5 (9) ◽  
pp. eaaw9162 ◽  
Author(s):  
Mandana T. Manzari ◽  
Grace R. Anderson ◽  
Kevin H. Lin ◽  
Ryan S. Soderquist ◽  
Merve Çakir ◽  
...  
Keyword(s):  
Small Molecule ◽  
Receptor Agonist ◽  
Death Receptor ◽  
Tumor Growth Inhibition ◽  
Cancer Therapies ◽  
Intrinsic Resistance ◽  
Extrinsic Pathway ◽  
Release Formulation ◽  
Sustained Release Formulation ◽  
Small Molecule Drugs

Extrinsic pathway agonists have failed repeatedly in the clinic for three core reasons: Inefficient ligand-induced receptor multimerization, poor pharmacokinetic properties, and tumor intrinsic resistance. Here, we address these factors by (i) using a highly potent death receptor agonist (DRA), (ii) developing an injectable depot for sustained DRA delivery, and (iii) leveraging a CRISPR-Cas9 knockout screen in DRA-resistant colorectal cancer (CRC) cells to identify functional drivers of resistance. Pharmacological blockade of XIAP and BCL-XL by targeted small-molecule drugs strongly enhanced the antitumor activity of DRA in CRC cell lines. Recombinant fusion of the DRA to a thermally responsive elastin-like polypeptide (ELP) creates a gel-like depot upon subcutaneous injection that abolishes tumors in DRA-sensitive Colo205 mouse xenografts. Combination of ELPdepot-DRA with BCL-XL and/or XIAP inhibitors led to tumor growth inhibition and extended survival in DRA-resistant patient-derived xenografts. This strategy provides a precision medicine approach to overcome similar challenges with other protein-based cancer therapies.

scholarly journals Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Zhigang Kang ◽  
Shi-Yong Sun ◽  
Liang Cao
Keyword(s):  
Skeletal Muscle ◽  
Therapeutic Strategy ◽  
Death Receptor ◽  
Suppressor Gene ◽  
Intrinsic Apoptosis ◽  
Extrinsic Pathway ◽  
Aggressive Management ◽  
Expression Of Genes ◽  
Extrinsic Apoptosis ◽  
Recombinant Trail

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such as MYOD1 and myogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in the p53 tumor suppressor gene. However, the ability to induce apoptosis via the death receptor-dependent extrinsic pathway remains largely intact in tumors with p53 mutations. This paper focuses on activating extrinsic apoptosis as a therapeutic strategy for RMS by targeting the death receptor DR5 with a recombinant TRAIL ligand or agonistic antibodies directed against DR5.

scholarly journals FAIM Is Regulated by MiR-206, MiR-1-3p and MiR-133b

2020 ◽  
Vol 8 ◽  
Author(s):  
Elena Coccia ◽  
Marc Masanas ◽  
Joaquín López-Soriano ◽  
Miguel F. Segura ◽  
Joan X. Comella ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Intrinsic Pathway ◽  
Extrinsic Pathway ◽  
Parkinson’S Diseases ◽  
Inhibitory Molecule ◽  
Death Receptor Signaling ◽  
Post Transcriptional Regulation

Apoptosis plays an important role during development, control of tissue homeostasis and in pathological contexts. Apoptosis is executed mainly through the intrinsic pathway or the death receptor pathway, i.e., extrinsic pathway. These processes are tightly controlled by positive and negative regulators that dictate pro- or anti-apoptotic death receptor signaling. One of these regulators is the Fas Apoptotic Inhibitory Molecule (FAIM). This death receptor antagonist has two main isoforms, FAIM-S (short) which is the ubiquitously expressed, and a longer isoform, FAIM-L (long), which is mainly expressed in the nervous system. Despite its role as a death receptor antagonist, FAIM also participates in cell death-independent processes such as nerve growth factor-induced neuritogenesis or synaptic transmission. Moreover, FAIM isoforms have been implicated in blocking the formation of protein aggregates under stress conditions or de-regulated in certain pathologies such as Alzheimer’s and Parkinson’s diseases. Despite the role of FAIM in physiological and pathological processes, little is known about the molecular mechanisms involved in the regulation of its expression. Here, we seek to investigate the post-transcriptional regulation of FAIM isoforms by microRNAs (miRNAs). We found that miR-206, miR-1-3p, and miR-133b are direct regulators of FAIM expression. These findings provide new insights into the regulation of FAIM and may provide new opportunities for therapeutic intervention in diseases in which the expression of FAIM is altered.

scholarly journals Stool-fermented Plantago ovata husk induces apoptosis in colorectal cancer cells independently of molecular phenotype

2011 ◽  
Vol 107 (11) ◽  
pp. 1591-1602 ◽  
Author(s):  
Vanessa R. Sohn ◽  
Anna Giros ◽  
Rosa M. Xicola ◽  
Lourdes Fluvià ◽  
Mike Grzybowski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
B Cell ◽  
Cell Lymphoma ◽  
Primary Tumour ◽  
Death Receptor ◽  
B Cell Lymphoma ◽  
Plantago Ovata ◽  
Extrinsic Pathway ◽  
Down Regulation ◽  
Lovo Cells

Several studies have suggested that the partially fermentable fibre Plantago ovata husk (PO) may have a protective effect on colorectal cancer (CRC). We studied the potentially pro-apoptotic effect of PO and the implicated mechanisms in CRC cells with different molecular phenotypes (Caco-2, HCT116, LoVo, HT-29, SW480) after PO anaerobic fermentation with colonic bacteria as it occurs in the human colon. The fermentation products of PO induced apoptosis in all primary tumour and metastatic cell lines, independent of p53, adenomatous polyposis coli, β-catenin or cyclo-oxygenase-2 status. Apoptosis was caspase-dependent and both intrinsic and extrinsic pathways were implicated. The intrinsic pathway was activated through a shift in the balance towards a pro-apoptotic environment with an up-regulation of B-cell lymphoma protein 2 homologous antagonist killer (BAK) and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) seen in HCT116 and LoVo cells. This resulted in mitochondrial membrane depolarisation, increased expression of caspase activators second mitochondria-derived activator of caspases (Smac)/Diablo, death effector apoptosis-inducing factor, apoptosome member apoptotic protease activating factor 1 and down-regulation of inhibitors of apoptosis Survivin and X-linked inhibitor of apoptosis in most cells. The extrinsic pathway was activated presumably through the up-regulation of death receptor (DR5). Some important differences were seen between primary tumour and metastatic CRC cells. Thus, metastatic PO-treated LoVo cells had a remarkable up-regulation of TNF-α ligand along with death-inducing signalling complex components receptor interacting protein and TNF-α receptor 1-associated death domain protein. The extrinsic pathway modulator FCICE-inhibitory protein (FLIP), an inhibitor of both spontaneous death ligand-independent and death receptor-mediated apoptosis, was significantly down-regulated after PO treatment in all primary tumour cells, but not in metastatic LoVo. These findings suggest that PO could potentially be a useful chemotherapy adjuvant.

scholarly journals Signaling through C/EBP Homologous Protein and Death Receptor 5 and Calpain Activation Differentially Regulate THP-1 Cell Maturation-Dependent Apoptosis Induced by Shiga Toxin Type 1

2010 ◽  
Vol 78 (8) ◽  
pp. 3378-3391 ◽  
Author(s):  
Moo-Seung Lee ◽  
Rama P. Cherla ◽  
Erin K. Lentz ◽  
Dinorah Leyva-Illades ◽  
Vernon L. Tesh
Keyword(s):  
Shiga Toxin ◽  
Death Receptor ◽  
Cell Maturation ◽  
Dependent Manner ◽  
Death Receptor 5 ◽  
Extrinsic Pathway ◽  
Calpain Activation ◽  
Homologous Protein ◽  
Induced Apoptosis

ABSTRACT Shiga toxins (Stxs) induce apoptosis via activation of the intrinsic and extrinsic pathways in many cell types. Toxin-mediated activation of the endoplasmic reticulum (ER) stress response was shown to be instrumental in initiating apoptosis in THP-1 myeloid leukemia cells. THP-1 cells responded to Shiga toxin type 1 (Stx1) in a cell maturation-dependent manner, undergoing rapid apoptosis in the undifferentiated state but reduced and delayed apoptosis in differentiated cells. The onset of apoptosis was associated with calpain activation and changes in expression of C/EBP homologous protein (CHOP), Bcl-2 family members, and death receptor 5 (DR5). Ligation of DR5 by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates the extrinsic pathway of apoptosis. We show here that expression of TRAIL and DR5 is increased by Stx1 treatment. Addition of exogenous TRAIL enhances, and anti-TRAIL antibodies inhibit, Stx1-induced apoptosis of THP-1 cells. Silencing of CHOP or DR5 expression selectively prevented caspase activation, loss of mitochondrial membrane potential, and Stx1-induced apoptosis of macrophage-like THP-1 cells. In contrast, the rapid kinetics of apoptosis induction in monocytic THP-1 cells correlated with rates of calpain cleavage. The results suggest that CHOP-DR5 signaling and calpain activation differentially contribute to cell maturation-dependent Stx1-induced apoptosis. Inhibition of these signaling pathways may protect cells from Stx cytotoxicity.

scholarly journals Apoptosis through Death Receptors in Temporal Lobe Epilepsy-Associated Hippocampal Sclerosis

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Marcelo Ananias Teocchi ◽  
Lília D’Souza-Li
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Hippocampal Sclerosis ◽  
Death Receptor ◽  
Death Receptors ◽  
Control Group ◽  
Extrinsic Pathway ◽  
Seizure Models ◽  
Pharmacological Studies ◽  
Encoding Genes

Seizure models have demonstrated that neuroinflammation and neurodegeneration are preponderant characteristics of epilepsy. Considering the lack of clinical studies, our aim is to investigate the extrinsic pathway of apoptosis in pharmacoresistant temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) patients, TLE(HS). By a specific death receptor-mediated apoptosis array plate, 31 upregulated targets were revealed in the sclerotic hippocampus from TLE(HS) patients. Amongst them are the encoding genes for ligands (FASLG,TNF,andTNFSF10) and death receptors (FAS,TNFRSF1A,TNFRSF10A,andTNFRSF10B). In addition, we evaluated the hippocampal relative mRNA expression of the two TNF receptors,TNFRSF1AandTNFRSF1B, in patients, being both upregulated (n=14;P<0.01andP<0.04, resp.) when compared to thepost mortemcontrol group (n=4). Our results have clearly suggested that three different death receptor apoptotic systems may be associated with the maintenance and progression of TLE-associated HS: (1) TNF-TNFRSF1A, (2) FASLG-FAS, and (3) TNFSF10-TNFRSF10A/B. Their effects on epilepsy are still scarcely comprehended. Our study points out to TNF and TNF receptor superfamily pathways as important targets for pharmacological studies regarding the benefits of an anti-inflammatory therapy in these patients.

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