Thermotolerance induced at a fever temperature of 40 °C protects cells against hyperthermia-induced apoptosis mediated by death receptor signalling

2008 ◽  
Vol 86 (6) ◽  
pp. 521-538 ◽  
Author(s):  
Ahmed Bettaieb ◽  
Diana A. Averill-Bates
Keyword(s):  
Chromatin Condensation ◽  
Death Receptor ◽  
Annexin V ◽  
Receptor Activation ◽  
Caspase 8 ◽  
Death Domain ◽  
Adaptive Responses ◽  
Receptor Signalling ◽  
Induced Apoptosis ◽  
Shock Proteins

Mild temperatures such as 40 °C are physiological and occur during fevers. This study determines whether mild thermotolerance induced at 40 °C can protect HeLa cells against activation of the death receptor pathway of apoptosis by lethal hyperthermia (42–45 °C). Protein expression of heat shock proteins (Hsps) 27, 32, 60, 72, 90, and 110 was increased in thermotolerant cells (3 h, 40°C). Lethal hyperthermia (42–43 °C)  caused cell death by apoptosis, but at 45 °C there was a switch to necrosis. Mild thermotolerance protected cells against heat-induced apoptosis (Annexin V labelling). Hyperthermia induced apoptosis through generation of reactive oxygen species (ROS) and death receptor signalling. The antioxidant polyethylene glycol-catalase abrogated increased expression of Fas death ligand and caspase-8 activation in response to lethal hyperthermia (42–43 °C). Mild thermotolerance attenuated the heat induction of ROS and FasL, which were initiating events in death receptor activation and signalling. Mild thermotolerance inhibited early events in hyperthermia-induced death receptor apoptosis such as Fas-associated death domain (FADD) translocation to membranes, caspase-8 activation, and tBid translocation to mitochondria. Downstream events in apoptosis such as caspase-3 activation, cleavage of PARP and ICAD, and chromatin condensation were also diminished in thermotolerant cells. It is important to improve knowledge about adaptive responses induced by exposure to mild stresses, such as fever temperatures, which can protect cells against subsequent exposure to lethal stress.

scholarly journals Sweet modification and regulation of death receptor signalling pathway

2021 ◽  
Author(s):  
Kenta Moriwaki ◽  
Francis K M Chan ◽  
Eiji Miyoshi
Keyword(s):  
Critical Role ◽  
Immune Surveillance ◽  
Death Receptor ◽  
Death Receptors ◽  
Receptor Activation ◽  
Intracellular Signalling ◽  
Human Diseases ◽  
Tumour Necrosis Factor Receptor ◽  
Death Domain ◽  
Receptor Signalling

Abstract Death receptors, members of the tumour necrosis factor receptor (TNFR) superfamily, are characterized by the presence of a death domain in the cytosolic region. TNFR1, Fas and TNF-related apoptosis-inducing ligand receptors, which are prototypical death receptors, exert pleiotropic functions in cell death, inflammation and immune surveillance. Hence, they are involved in several human diseases. The activation of death receptors and downstream intracellular signalling is regulated by various posttranslational modifications, such as phosphorylation, ubiquitination and glycosylation. Glycosylation is one of the most abundant and versatile modifications to proteins and lipids, and it plays a critical role in the development and physiology of organisms, as well as the pathology of many human diseases. Glycans control a number of cellular events, such as receptor activation, signal transduction, endocytosis, cell recognition and cell adhesion. It has been demonstrated that oligo- and monosaccharides modify death receptors and intracellular signalling proteins and regulate their functions. Here, we review the current understanding of glycan modifications of death receptor signalling and their impact on signalling activity.

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 A New Caspase-8 Isoform Caspase-8s Increased Sensitivity to Apoptosis in Jurkat Cells

2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Zhifang Xu ◽  
Kejing Tang ◽  
Min Wang ◽  
Qing Rao ◽  
Bolin Liu ◽  
...  
Keyword(s):  
Death Receptor ◽  
Adaptor Protein ◽  
Jurkat Cells ◽  
Caspase 8 ◽  
Death Domain ◽  
Binding Assays ◽  
Increased Sensitivity ◽  
Death Effector ◽  
Induced Apoptosis

Caspase-8 is a key initiator of death receptor-induced apoptosis. Here we report a novel short isoform of caspase-8 (caspase-8s), which encodes the first (Death Effector Domain) DED and part of the second DED, missing the C-terminal caspase domain. In vivo binding assays showed that transfected caspase-8s bound to (Fas-associated death domain protein) FADD, the adaptor protein in (death-induced signal complex) DISC. To investigate the potential effects of caspase-8s on cell apoptosis, Jurkat cells were stably transfected with caspase-8s. Overexpression of caspase-8s increased sensitivity to the apoptotic stimuli, Fas-agonistic antibody CH11. These results suggest that caspase-8s may act as a promoter of apoptosis through binding to FADD and is involved in the regulation of apoptosis. In addition, the results also indicate that the first DED was an important structure mediating combination between caspase-8 and FADD.

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.

Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

2021 ◽  
Author(s):  
Kanchana Suksri ◽  
Namoiy Semprasert ◽  
Mutita Junking ◽  
Suchanoot Kutpruek ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Death Receptor ◽  
Caspase 8 ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

scholarly journals Death Receptor-Induced Activation of Initiator Caspase 8 Is Antagonized by Serine/Threonine Kinase PAK4

2003 ◽  
Vol 23 (21) ◽  
pp. 7838-7848 ◽  
Author(s):  
Nerina Gnesutta ◽  
Audrey Minden
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Intracellular Signaling ◽  
Death Receptor ◽  
Caspase 8 ◽  
Death Domain ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Different Types ◽  
Promote Cell Survival

ABSTRACT Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling proteins regulate apoptosis, or programmed cell death, other proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic protein Bad. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK proteins and suggests a new mechanism by which these proteins promote cell survival.

scholarly journals RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions

2014 ◽  
Vol 5 (12) ◽  
pp. e1555-e1555 ◽  
Author(s):  
Y Estornes ◽  
M A Aguileta ◽  
C Dubuisson ◽  
J De Keyser ◽  
V Goossens ◽  
...  
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Life And Death ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)—a kinase at the crossroad between life and death downstream of various receptors—as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1).

scholarly journals Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform

2019 ◽  
Vol 15 (9) ◽  
pp. e1007374 ◽  
Author(s):  
Anna Matveeva ◽  
Michael Fichtner ◽  
Katherine McAllister ◽  
Christopher McCann ◽  
Marc Sturrock ◽  
...  
Keyword(s):  
Death Receptor ◽  
Receptor Activation ◽  
Molecular Assembly ◽  
Caspase 8 ◽  
Low Level
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