Upon Drug-Induced Apoptosis Expression of Prostate-apoptosis-response-gene-4 Promotes Cleavage of Caspase-8, Bid and Mitochondrial Release of Cytochrome c

Hematology ◽  
2004 ◽  
Vol 9 (5-6) ◽  
pp. 425-431 ◽  
Author(s):  
Simone Boehrer ◽  
Natasa Kukoc-Zivojnov ◽  
Daniel Nowak ◽  
Marion Bergmann ◽  
Christine Baum ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Caspase 8 ◽  
Response Gene ◽  
Drug Induced ◽  
Induced Apoptosis ◽  
Gene 4

Prostate-Apoptosis-Response-Gene-4 Increases Sensitivity to TRAIL-Induced Apoptosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2485-2485
Author(s):  
Simone Boehrer ◽  
Daniel Nowak ◽  
Elena Puccetti ◽  
Martin Ruthardt ◽  
Nicole Sattler ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Jurkat Cells ◽  
Caspase 8 ◽  
Response Gene ◽  
Normal Tissues ◽  
Molecular Determinants ◽  
Initiator Caspases ◽  
Subsequent Activation ◽  
Induced Apoptosis ◽  
Gene 4

Abstract The capacity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to preferentially induce apoptosis in malignant cells while sparing normal tissues renders it an attractive therapeutic agent. Nevertheless, the molecular determinants governing sensitivity towards TRAIL remain to be defined. Acknowledging the previously demonstrated deregulation of prostate-apoptosis-response-gene-4 (par-4) in ex vivo cells of patients suffering from acute and chronic lymphatic leukemia, we here tested the hypothesis that expression of par-4 influences sensitivity to TRAIL. We here show, that expression of par-4 in T-lymphoblastic Jurkat cells i) considerably increases TRAIL-induced apoptosis; ii) enforces cleavage of c-FlipL and the subsequent activation of the initiator caspases-8 and -10; iii) does not alter expression of the Bcl-2 family members Bax and Bak; iv) does not enhance the disruption of mitochondrial membrane potential; v) promotes down-regulation the inhibitor-of-apoptosis proteins cIAP-1, cIAP-2, XIAP and survivin; vi) concomitantly augments activation of the executioner caspases-6 and -7. Moreover we prove the crucial role of caspase-8 in par-4-promoted apoptosis by demonstrating that inhibition of caspase-8 considerably reduces TRAIL-induced apoptosis in mock- as well as par-4-transfected Jurkat clones and reverses the described molecular changes. In conclusion, we here provide first evidence that expression of par-4 determines sensitivity to TRAIL-induced lymphocytic cell death and outline the responsible molecular determinants.

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 Contribution of Mitochondrial Ion Channels to Chemo-Resistance in Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 761 ◽  
Author(s):  
Roberta Peruzzo ◽  
Ildiko Szabo
Keyword(s):  
Ion Channels ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
Point Of No Return ◽  
Different Types ◽  
Subsequent Activation ◽  
Induced Apoptosis ◽  
Potential Efficiency

Mitochondrial ion channels are emerging oncological targets, as modulation of these ion-transporting proteins may impact on mitochondrial membrane potential, efficiency of oxidative phosphorylation and reactive oxygen production. In turn, these factors affect the release of cytochrome c, which is the point of no return during mitochondrial apoptosis. Many of the currently used chemotherapeutics induce programmed cell death causing damage to DNA and subsequent activation of p53-dependent pathways that finally leads to cytochrome c release from the mitochondrial inter-membrane space. The view is emerging, as summarized in the present review, that ion channels located in this organelle may account in several cases for the resistance that cancer cells can develop against classical chemotherapeutics, by preventing drug-induced apoptosis. Thus, pharmacological modulation of these channel activities might be beneficial to fight chemo-resistance of different types of cancer cells.

Functional CD95 ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 301-308 ◽  
Author(s):  
Simone Fulda ◽  
Gudrun Strauss ◽  
Eric Meyer ◽  
Klaus-Michael Debatin
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Leukemia Cell Line ◽  
Receptor Interaction ◽  
Caspase 8 ◽  
Drug Induced ◽  
Signaling Complex ◽  
Cd95 Ligand ◽  
Activation Induced Cell Death ◽  
Induced Apoptosis

Abstract Activation-induced cell death (AICD) in T cells is mediated by CD95 ligand (CD95L)/receptor interaction, which has also been implicated in apoptosis induction by some anticancer agents. In this article we show that both anti-CD3-triggering (AICD) and doxorubicin treatment led to the production of a functionally active CD95L in the CD3+/T-cell receptor-positive (TCR+) T leukemia cell line H9. CD95L-expressing H9 cells killed CD95-sensitive J16 or CEM target cells, but not CD95-resistant CEM or J16 cells overexpressing dominant negative FADD (J16/FADD-DN). By immunoprecipitation, CD95L was physically bound to CD95, suggesting that AICD and doxorubicin-induced apoptosis involve CD95L-mediated CD95 aggregation, thereby triggering the CD95 death pathway. CD95 aggregation was associated with the recruitment of FADD and caspase-8 to the CD95 receptor to form the CD95 death-inducing signaling complex (DISC), resulting in caspase-8 activation and cleavage of the effector caspase-3 and PARP. Blocking of the CD95L/receptor interaction by antagonistic antibodies to CD95 or to CD95L also blocked AICD and inhibited the early phase of doxorubicin-induced apoptosis, though cell death induced by doxorubicin eventually proceeded in a CD95-independent manner. These findings may explain some conflicting data on the role of death receptor systems in drug-induced apoptosis. Thus, in cells with an inducible CD95 receptor/ligand system, drug-induced apoptosis may be mediated by CD95L-initiated DISC formation and activation of downstream effector programs similar to AICD in T cells. (Blood. 2000;95:301-308)

scholarly journals Caspase-8 Can Be Activated by Interchain Proteolysis without Receptor-triggered Dimerization during Drug-induced Apoptosis

2004 ◽  
Vol 280 (7) ◽  
pp. 5267-5273 ◽  
Author(s):  
Dennis Sohn ◽  
Klaus Schulze-Osthoff ◽  
Reiner U. Jänicke
Keyword(s):  
Caspase 8 ◽  
Drug Induced ◽  
Induced Apoptosis

scholarly journals Autoregulatory Feedback Mechanism of P38MAPK/Caspase-8 in Photodynamic Therapy-Hydrophilic/Lipophilic Tetra-α-(4-carboxyphenoxy) Phthalocyanine Zinc-Induced Apoptosis of Human Hepatocellular Carcinoma Bel-7402 Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Yu Wang ◽  
Chunhui Xia ◽  
Wei Chen ◽  
Yuhang Chen ◽  
Yiyi Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Photodynamic Therapy ◽  
Membrane Potential ◽  
Cytochrome C ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Human Hepatocellular Carcinoma ◽  
Caspase 8 ◽  
Induced Apoptosis

Photodynamic therapy (PDT) is a novel and promising antitumor treatment. Our previous study showed that hydrophilic/lipophilic tetra-α-(4-carboxyphenoxy) phthalocyanine zinc- (TαPcZn-) mediated PDT (TαPcZn-PDT) inhibits the proliferation of human hepatocellular carcinoma Bel-7402 cells by triggering apoptosis and arresting cell cycle. However, mechanisms of TαPcZn-PDT-induced apoptosis of Bel-7402 cells have not been fully clarified. In the present study, therefore, effect of TαPcZn-PDT on apoptosis, P38MAPK, p-P38MAPK, Caspase-8, Caspase-3, Bcl-2, Bid, Cytochrome c, and mitochondria membrane potential in Bel-7402 cells without or with P38MAPK inhibitor SB203580 or Caspase-8 inhibitor Ac-IEFD-CHO was investigated by haematoxylin and eosin (HE) staining assay, flow cytometry analysis of annexin V-FITC/propidium iodide (PI) double staining cells and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1), and immunoblot assay. We found that TαPcZn-PDT resulted in apoptosis induction, activation of P38MAPK, Caspase-8, Caspase-3, and Bid, downregulation of Bcl-2, release of Cytochrome c from mitochondria, and disruption of mitochondrial membrane potential in TαPcZn-PDT-treated Bel-7402 cells. In contrast, SB203580 or Ac-IEFD-CHO attenuated induction of apoptosis, activation of P38MAPK, Caspase-8, Caspase-3, and Bid, downregulation of Bcl-2, release of Cytochrome c from mitochondria, and disruption of mitochondrial membrane potential in TαPcZn-PDT-treated Bel-7402 cells. Taken together, we conclude that Caspase-3, Bcl-2, Bid, and mitochondria are involved in autoregulatory feedback of P38MAPK/Caspase-8 during TαPcZn-PDT-induced apoptosis of Bel-7402 cells.

Prostate-apoptosis-response-gene-4 increases sensitivity to TRAIL-induced apoptosis

2006 ◽  
Vol 30 (5) ◽  
pp. 597-605 ◽  
Author(s):  
Simone Boehrer ◽  
Daniel Nowak ◽  
Elena Puccetti ◽  
Martin Ruthardt ◽  
Nicole Sattler ◽  
...  
Keyword(s):  
Response Gene ◽  
Induced Apoptosis ◽  
Gene 4
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