scholarly journals Anticancer Drugs Induce Caspase-8/FLICE Activation and Apoptosis in the Absence of CD95 Receptor/Ligand Interaction

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 3053-3063 ◽  
Author(s):  
Sebastian Wesselborg ◽  
Ingo H. Engels ◽  
Evi Rossmann ◽  
Marek Los ◽  
Klaus Schulze-Osthoff
Keyword(s):  
Anticancer Drugs ◽  
De Novo ◽  
Death Receptor ◽  
Dominant Negative ◽  
Caspase 8 ◽  
Drug Induced ◽  
Ligand Interaction ◽  
Caspase Family ◽  
Death Receptor Signaling ◽  
Induced Apoptosis

Abstract Proteases of the caspase family are the critical executioners of apoptosis. Their activation has been mainly studied upon triggering of death receptors, such as CD95 (Fas/APO-1) and tumor necrosis factor-R1, which recruit caspase-8/FLICE as the most proximal effector to the receptor complex. Because apoptosis induced by anticancer drugs has been proposed to involve CD95/CD95 ligand interaction, we investigated the mechanism of caspase activation by daunorubicin, doxorubicin, etoposide, and mitomycin C. In Jurkat leukemic T cells, all drugs induced apoptosis and the cleavage of procaspase-8 to its active p18 subunit. However, cells resistant to CD95 were equally susceptible to anticancer drugs and activated caspase-8 with a similar kinetic and dose response as CD95-sensitive cells. The broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis and caspase-8 activation in response to CD95 and drug treatment, whereas a neutralizing CD95 decoy as well as a dominant-negative FADD construct selectively abrogated CD95, but not drug-induced effects. A potent activation of caspase-8 was also induced by cycloheximide, indicating that it was independent of protein synthesis. Our data, therefore, show that (1) anticancer drug-induced apoptosis does not require de novo synthesis of death ligands or CD95 interaction, and (2) that caspase-8 can be activated in the absence of a death receptor signaling.

scholarly journals Anticancer Drugs Induce Caspase-8/FLICE Activation and Apoptosis in the Absence of CD95 Receptor/Ligand Interaction

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 3053-3063 ◽  
Author(s):  
Sebastian Wesselborg ◽  
Ingo H. Engels ◽  
Evi Rossmann ◽  
Marek Los ◽  
Klaus Schulze-Osthoff
Keyword(s):  
Anticancer Drugs ◽  
De Novo ◽  
Death Receptor ◽  
Dominant Negative ◽  
Caspase 8 ◽  
Drug Induced ◽  
Ligand Interaction ◽  
Caspase Family ◽  
Death Receptor Signaling ◽  
Induced Apoptosis

Proteases of the caspase family are the critical executioners of apoptosis. Their activation has been mainly studied upon triggering of death receptors, such as CD95 (Fas/APO-1) and tumor necrosis factor-R1, which recruit caspase-8/FLICE as the most proximal effector to the receptor complex. Because apoptosis induced by anticancer drugs has been proposed to involve CD95/CD95 ligand interaction, we investigated the mechanism of caspase activation by daunorubicin, doxorubicin, etoposide, and mitomycin C. In Jurkat leukemic T cells, all drugs induced apoptosis and the cleavage of procaspase-8 to its active p18 subunit. However, cells resistant to CD95 were equally susceptible to anticancer drugs and activated caspase-8 with a similar kinetic and dose response as CD95-sensitive cells. The broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis and caspase-8 activation in response to CD95 and drug treatment, whereas a neutralizing CD95 decoy as well as a dominant-negative FADD construct selectively abrogated CD95, but not drug-induced effects. A potent activation of caspase-8 was also induced by cycloheximide, indicating that it was independent of protein synthesis. Our data, therefore, show that (1) anticancer drug-induced apoptosis does not require de novo synthesis of death ligands or CD95 interaction, and (2) that caspase-8 can be activated in the absence of a death receptor signaling.

Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3

Blood ◽  
2001 ◽  
Vol 97 (5) ◽  
pp. 1378-1387 ◽  
Author(s):  
Thomas Wieder ◽  
Frank Essmann ◽  
Aram Prokop ◽  
Karin Schmelz ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Death Receptor ◽  
Lymphoid Cells ◽  
Caspase 8 ◽  
Lymphoma Cells ◽  
Drug Induced ◽  
Ligand Interaction ◽  
B Lymphoma ◽  
B Lymphoma Cells ◽  
Induced Apoptosis

The activation of caspase-8, a crucial upstream mediator of death receptor signaling, was investigated in epirubicin- and Taxol-induced apoptosis of B-lymphoma cells. This study was performed because the CD95/Fas receptor-ligand interaction, recruitment of the Fas-associated death domain (FADD) adaptor protein, and subsequent activation of procaspase-8 have been implicated in the execution of drug-induced apoptosis in other cell types. Indeed, active caspase-8 was readily detected after treatment of mature and immature B-lymphoid cells with epirubicin or Taxol. However, neither constitutive nor drug-induced expression of the CD95/Fas ligand was detectable in B-lymphoma cells. Furthermore, overexpression of a dominant-negative FADD mutant (FADDdn) did not block caspase-8 processing and subsequent DNA fragmentation, indicating that drug-induced caspase-8 activation was mediated by a CD95/Fas-independent mechanism. Instead, caspase-8 cleavage was slightly preceded by activation of caspase-3, suggesting that drug-induced caspase-8 activation in B-lymphoma cells is a downstream event mediated by other caspases. This assumption was confirmed in 2 experimental systems—zDEVD-fmk, a cell-permeable inhibitor of caspase-3–like activity, blocked drug-induced caspase-8 cleavage, and depletion of caspase-3 from cell extracts impaired caspase-8 cleavage after in vitro activation with dATP and cytochrome c. Thus, these data indicate that drug-induced caspase-8 activation in B-lymphoma cells is independent of death receptor signaling and is mediated by postmitochondrial caspase-3 activation.

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 Sulphureuine B, a drimane type sesquiterpenoid isolated from Laetiporus sulphureus induces apoptosis in glioma cells

2015 ◽  
Vol 10 (4) ◽  
pp. 844 ◽  
Author(s):  
Jing-Wei Zhang ◽  
Gong-Ling Wen ◽  
Lei Zhang ◽  
Dong-Mei Duan ◽  
Zhong-Hai Ren
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Signaling Pathways ◽  
Death Receptor ◽  
Glioma Cells ◽  
Edible Mushroom ◽  
Caspase 8 ◽  
Laetiporus Sulphureus ◽  
Death Receptor Signaling ◽  
Induced Apoptosis

<p class="Abstract">A drimane type sesquiterpenoids, sulphureuine B was isolated from the edible mushroom <em>Laetiporus sulphureus</em> and its antiproliferative properties were investigated using U-87MG glioma cells. It was observed that sulphu-reuine B-induced apoptosis in U-87MG cells and the mechanisms involved are endoplasmic reticulum stress, mitochondrial and death receptor mediated pathways. Endoplasmic reticulum stress was identified from the results of enormous cytoplasmic vacuolation, CHOP elevation and caspase-12 cleavage. Further, we found that treatment of sulphureuine B-induced PERK, IRE1α, and ATF6α activations. In addition, sulphureuine B-induced Bcl-2 down-regulation, cleavage of PARP, and caspase-8 activation were also affected. All these experimental results clearly revealed that sulphureuine B-induced apoptosis mediated through endoplasmic reticulum stress, mitochondrial, and death receptor signaling pathways.</p><p> </p>

scholarly journals Differential Regulation and ATP Requirement for Caspase-8 and Caspase-3 Activation during CD95- and Anticancer Drug–induced Apoptosis

1998 ◽  
Vol 188 (5) ◽  
pp. 979-984 ◽  
Author(s):  
Davide Ferrari ◽  
Ania Stepczynska ◽  
Marek Los ◽  
Sebastian Wesselborg ◽  
Klaus Schulze-Osthoff
Keyword(s):  
Death Receptor ◽  
Mitochondrial Pathway ◽  
Atp Depletion ◽  
Caspase 8 ◽  
Chemotherapeutic Drugs ◽  
Caspase Activation ◽  
Drug Induced ◽  
Regulatory Pathways ◽  
Atp Production ◽  
Induced Apoptosis

Apoptosis is induced by different stimuli, among them triggering of the death receptor CD95, staurosporine, and chemotherapeutic drugs. In all cases, apoptosis is mediated by caspases, although it is unclear how these diverse apoptotic stimuli cause protease activation. Two regulatory pathways have been recently identified, but it remains unknown whether they are functionally independent or linked to each other. One is mediated by recruitment of the proximal regulator caspase-8 to the death receptor complex. The other pathway is controlled by the release of cytochrome c from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Here, we report that both pathways can be dissected by depletion of intracellular ATP. Prevention of ATP production completely inhibited caspase activation and apoptosis in response to chemotherapeutic drugs and staurosporine. Interestingly, caspase-8, whose function appeared to be restricted to death receptors, was also activated by these drugs under normal conditions, but not after ATP depletion. In contrast, inhibition of ATP production did not affect caspase activation after triggering of CD95. These results suggest that chemotherapeutic drug–induced caspase activation is entirely controlled by a receptor-independent mitochondrial pathway, whereas CD95-induced apoptosis can be regulated by a separate pathway not requiring Apaf-1 function.

scholarly journals Caspase Activation by Adenovirus E4orf4 Protein Is Cell Line Specific and Is Mediated by the Death Receptor Pathway

2001 ◽  
Vol 75 (2) ◽  
pp. 789-798 ◽  
Author(s):  
Adi Livne ◽  
Ronit Shtrichman ◽  
Tamar Kleinberger
Keyword(s):  
Death Receptor ◽  
Dominant Negative ◽  
Disulfonic Acid ◽  
Ros Generation ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase Activation ◽  
Apoptotic Pathway ◽  
Death Receptor Pathway ◽  
Induced Apoptosis

ABSTRACT Adenovirus E4orf4 protein has been shown to induce transformed cell-specific, protein phosphatase 2A-dependent, and p53-independent apoptosis. It has been further reported that the E4orf4 apoptotic pathway is caspase-independent in CHO cells. Here, we show that E4orf4 induces caspase activation in the human cell lines H1299 and 293T. Caspase activation is required for apoptosis in 293T cells, but not in H1299 cells. Dominant negative mutants of caspase-8 and the death receptor adapter protein FADD/MORT1 inhibit E4orf4-induced apoptosis in 293T cells, suggesting that E4orf4 activates the death receptor pathway. Cytochrome c is released into the cytosol in E4orf4-expressing cells, but caspase-9 is not required for induction of apoptosis. Furthermore, E4orf4 induces accumulation of reactive oxygen species (ROS) in a caspase-8- and FADD/MORT1-dependent manner, and inhibition of ROS generation by 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron) inhibits E4orf4-induced apoptosis. Thus, our results demonstrate that E4orf4 engages the death receptor pathway to generate at least part of the molecular events required for E4orf4-induced apoptosis.

Arsenic Trioxide Induces Regulated, Death Receptor- and Caspase-Independent Cell Death through the Mitochondrial Death Pathway.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4421-4421
Author(s):  
Christian Scholz ◽  
Antje Richter ◽  
Mario Lehmann ◽  
Klaus Schulze-Osthoff ◽  
Bernd Dörken ◽  
...  
Keyword(s):  
Cell Death ◽  
Arsenic Trioxide ◽  
Death Receptor ◽  
Specific Inhibitor ◽  
Mitochondrial Pathway ◽  
Dominant Negative ◽  
Lymphoid Cells ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Ligand Interaction

Abstract Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There, and in lymphoid cells we demonstrated that arsenite induces cell death in a caspase-2 and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death inducing signaling complex in arsenite-induced cell death. In detail, we demonstrate that arsenite induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As2O3-induced cell death was not blocked by the broad spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETD-fmk. Nevertheless, arsenite-induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, arsenite-induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As2O3-induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2 controlled mitochondrial pathway that does, however, not rely on caspase-9.

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.

Beyond apoptosis: nonapoptotic cell death in physiology and disease

2005 ◽  
Vol 83 (5) ◽  
pp. 579-588 ◽  
Author(s):  
Claudio A Hetz ◽  
Vicente Torres ◽  
Andrew F.G Quest
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Death Receptor ◽  
Receptor Signaling ◽  
Family Analysis ◽  
Caspase Family ◽  
Death Receptor Signaling ◽  
Apoptotic Pathways ◽  
Nonapoptotic Cell Death ◽  
High Degree

Apoptosis is a morphologically defined form of programmed cell death (PCD) that is mediated by the activation of members of the caspase family. Analysis of death-receptor signaling in lymphocytes has revealed that caspase-dependent signaling pathways are also linked to cell death by nonapoptotic mechanisms, indicating that apoptosis is not the only form of PCD. Under physiological and pathological conditions, cells demonstrate a high degree of flexibility in cell-death responses, as is reflected in the existence of a variety of mechanisms, including necrosis-like PCD, autophagy (or type II PCD), and accidental necrosis. In this review, we discuss recent data suggesting that canonical apoptotic pathways, including death-receptor signaling, control caspase-dependent and -independent cell-death pathways.Key words: apoptosis, necrosis, nonapoptotic programmed cell death, death receptors, ceramides.

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