The Experts below are selected from a list of 111066 Experts worldwide ranked by ideXlab platform
Shi-yong Sun - One of the best experts on this subject based on the ideXlab platform.
-
Understanding the Role of the Death Receptor 5/FADD/caspase-8 Death Signaling in Cancer Metastasis.
Molecular and cellular pharmacology, 2011Co-Authors: Shi-yong SunAbstract:The normal function of the extrinsic apoptotic pathway is to mediate apoptosis. Thus, this pathway is generally recognized to be critical in host immune surveillance against cancer. However, many studies have suggested that some key components in this pathway including Fas, Death Receptor 5 (DR5), Fas-associated Death domain (FADD) and caspase-8 may contribute to cancer growth or metastasis. Our recent study on DR5 and caspase-8 expression in human head and neck cancer tissues indicate that high caspase-8 either alone or along with high DR5 in tumor tissue from patients with lymph node metastasis is significantly associated with poor disease-free survival and overall survival, suggesting that these proteins may be involved in positive regulation of cancer metastasis. Thus, efforts should be made to better understand the role of the Death Receptor 5/FADD/caspase-8 Death signaling in regulation of cancer metastasis.
-
understanding the role of the Death Receptor 5 fadd caspase 8 Death signaling in cancer metastasis
Molecular and Cellular Pharmacology, 2011Co-Authors: Shi-yong SunAbstract:The normal function of the extrinsic apoptotic pathway is to mediate apoptosis. Thus, this pathway is generally recognized to be critical in host immune surveillance against cancer. However, many studies have suggested that some key components in this pathway including Fas, Death Receptor 5 (DR5), Fas-associated Death domain (FADD) and caspase-8 may contribute to cancer growth or metastasis. Our recent study on DR5 and caspase-8 expression in human head and neck cancer tissues indicate that high caspase-8 either alone or along with high DR5 in tumor tissue from patients with lymph node metastasis is significantly associated with poor disease-free survival and overall survival, suggesting that these proteins may be involved in positive regulation of cancer metastasis. Thus, efforts should be made to better understand the role of the Death Receptor 5/FADD/caspase-8 Death signaling in regulation of cancer metastasis.
-
Death Receptor regulation and celecoxib induced apoptosis in human lung cancer cells
Journal of the National Cancer Institute, 2004Co-Authors: Xiangguo Liu, Ping Yue, Zhongmei Zhou, Fadlo R Khuri, Shi-yong SunAbstract:Background: Celecoxib, a cyclooxygenase 2 inhibitor, has chemopreventive and therapeutic activities toward lung cancer and other epithelial malignancies. Celecoxib can induce apoptosis in various cancer cell lines through a mechanism that is independent of its cyclooxygenase 2 inhibitory activity but is otherwise largely uncharacterized. We investigated the mechanism of celecoxib-induced apoptosis further. Methods: All experiments were conducted in human non-small-cell lung carcinoma (NSCLC) cell lines; results in celecoxibtreated and untreated cells were compared. Cell survival was assessed with a sulforhodamine B assay. Apoptosis was assessed by DNA fragmentation with an enzyme-linked immunosorbent assay, by terminal deoxynucleotidyltransferase- mediated dUTP nick-end-labeling (TUNEL) assay, and by western blot analysis of caspase activation. Death Receptor gene and protein expression was detected by northern and western blot analysis, respectively. Gene silencing was achieved with small interfering RNA (siRNA) technology. Results: Celecoxib treatment decreased cell survival, activated caspase cascades, and increased DNA fragmentation, all of which were abrogated when caspase 8 expression was silenced with caspase 8 siRNA. Celecoxib treatment induced the expression of Death Receptors, particularly that of DR5. Overexpression of a dominant negative Fas-associated Death domain mutant, but not of BCL2, reduced the level of celecoxib-induced apoptosis, and silencing of DR5 expression by DR5 siRNA suppressed celecoxib-induced caspase 8 activation and apoptosis. Combination treatment with celecoxib and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced additional apoptosis. For example, survival of A549 cells was decreased with 50 μM celecoxib alone by 38.7% (95% confidence interval [CI] = 35.2% to 42.2%), with TRAIL alone by 29.3% (95% CI = 25.1% to 33.6%), but with their combination by 77.5% (95% CI = 74.5% to 79.5%), a greater than additive effect. Conclusion: Celecoxib appears to induce apoptosis in human NSCLC through the extrinsic Death Receptor pathway.
Jonathan N. Sachs - One of the best experts on this subject based on the ideXlab platform.
-
Noncompetitive Allosteric Antagonism of Death Receptor 5 by a Synthetic Affibody Ligand.
Biochemistry, 2020Co-Authors: Nagamani Vunnam, Sophia Szymonski, Petra Hirsova, Gregory J. Gores, Jonathan N. Sachs, Benjamin J. HackelAbstract:Fatty acid-induced upregulation of Death Receptor 5 (DR5) and its cognate ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), promotes hepatocyte lipoapoptosis, which is a key ...
-
soluble extracellular domain of Death Receptor 5 inhibits trail induced apoptosis by disrupting Receptor Receptor interactions
Journal of Molecular Biology, 2017Co-Authors: Nagamani Vunnam, David D. Thomas, Benjamin D. Grant, Jonathan N. SachsAbstract:Abstract Dysregulation of tumor necrosis factor (TNF) Receptor signaling is a key feature of various inflammatory disorders. Current treatments for TNF-related diseases function either by sequestering ligand or blocking ligand–Receptor interactions, which can cause dangerous side effects by inhibiting the Receptors that are not involved in the disease condition. Thus, alternate strategies that target Receptor–Receptor interactions are needed. We hypothesized that the soluble extracellular domain (ECD) of long isoform of Death Receptor 5 (DR5) could block endogenous Receptor assembly, mimicking the biological effect of decoy Receptors that lack the Death domain to trigger apoptosis. Using live-cell fluorescence resonance energy transfer studies, we demonstrated that soluble ECD disrupts endogenous DR5–DR5 interactions. Cell viability assays were used to demonstrate the complete inhibition of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the ECD, although TRAIL is still able to bind to the Receptor. Importantly, we used mutagenesis to prove that the inhibition of TRAIL-induced apoptosis by the ECD predominantly comes from the disruption of DR5 oligomerization and not ligand sequestration. Inhibition of Death Receptor activation should have important therapeutic applications in diseases such as nonalcoholic fatty liver disease. More generally, this approach should be generalized to enable the inhibition of other TNF Receptor signaling mechanisms that are associated in a wide range of clinical conditions.
-
Death Receptor 5 Activation Is Energetically Coupled to Opening of the Transmembrane Domain Dimer
Biophysical Journal, 2017Co-Authors: Nagamani Vunnam, Cecily K. Campbell-bezat, Andrew K. Lewis, Jonathan N. SachsAbstract:Abstract The precise mechanism by which binding of tumor necrosis factor ligands to the extracellular domain of their corresponding Receptors transmits signals across the plasma membrane has remained elusive. Recent studies have proposed that activation of several tumor necrosis factor Receptors, including Death Receptor 5, involves a scissorlike opening of the disulfide-linked transmembrane (TM) dimer. Using time-resolved fluorescence resonance energy transfer, we provide, to our knowledge, the first direct biophysical evidence that Death Receptor 5 TM-dimers open in response to ligand binding. Then, to probe the importance of the closed-to-open TM domain transition in the overall energetics of Receptor activation, we designed point-mutants (alanine to phenylalanine) in the predicted, tightly packed TM domain dimer interface. We hypothesized that the bulky residues should destabilize the closed conformation and eliminate the ∼3 kcal/mol energy barrier to TM domain opening and the ∼2 kcal/mol energy difference between the closed and open states, thus oversensitizing the Receptor. To test this, we used all-atom molecular dynamics simulations of the isolated TM domain in explicit lipid bilayers coupled to thermodynamic potential of mean force calculations. We showed that single point mutants at the interface altered the energy landscape as predicted, but were not enough to completely eliminate the barrier to opening. However, the computational model did predict that a double mutation at i , i +4 positions at the center of the TM domain dimer eliminates the barrier and stabilizes the open conformation relative to the closed. We tested these mutants in cells with time-resolved fluorescence resonance energy transfer and Death assays, and show remarkable agreement with the calculations. The single mutants had a small effect on TM domain separation and cell Death, whereas the double mutant significantly increased the TM domain separation and more than doubled the sensitivity of cells to ligand stimulation.
-
Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor–Receptor Interactions
Journal of Molecular Biology, 2017Co-Authors: Nagamani Vunnam, David D. Thomas, Benjamin D. Grant, Jonathan N. SachsAbstract:Abstract Dysregulation of tumor necrosis factor (TNF) Receptor signaling is a key feature of various inflammatory disorders. Current treatments for TNF-related diseases function either by sequestering ligand or blocking ligand–Receptor interactions, which can cause dangerous side effects by inhibiting the Receptors that are not involved in the disease condition. Thus, alternate strategies that target Receptor–Receptor interactions are needed. We hypothesized that the soluble extracellular domain (ECD) of long isoform of Death Receptor 5 (DR5) could block endogenous Receptor assembly, mimicking the biological effect of decoy Receptors that lack the Death domain to trigger apoptosis. Using live-cell fluorescence resonance energy transfer studies, we demonstrated that soluble ECD disrupts endogenous DR5–DR5 interactions. Cell viability assays were used to demonstrate the complete inhibition of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the ECD, although TRAIL is still able to bind to the Receptor. Importantly, we used mutagenesis to prove that the inhibition of TRAIL-induced apoptosis by the ECD predominantly comes from the disruption of DR5 oligomerization and not ligand sequestration. Inhibition of Death Receptor activation should have important therapeutic applications in diseases such as nonalcoholic fatty liver disease. More generally, this approach should be generalized to enable the inhibition of other TNF Receptor signaling mechanisms that are associated in a wide range of clinical conditions.
Klaus-michael Debatin - One of the best experts on this subject based on the ideXlab platform.
-
Exploiting Death Receptor signaling pathways for tumor therapy
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2004Co-Authors: Simone Fulda, Klaus-michael DebatinAbstract:Apoptosis or programmed cell Death is a key regulator of physiological growth control and regulation of tissue homeostasis. Tipping the balance between cell Death and proliferation in favor of cell survival may result in tumor formation. Moreover, current cancer therapies, e.g. chemotherapy, gamma-irradiation, immunotherapy or suicide gene therapy, primarily exert their antitumor effect by triggering an evolutionary conserved apoptosis program in cancer cells. For example, Death Receptor signaling has been implied to contribute to the efficacy of cancer therapy. Thus, failure to undergo apoptosis in response to anticancer therapy because of defects in Death Receptor pathways may result in resistance. Further insights into the mechanisms regulating apoptosis in response to anticancer therapy and how cancer cells evade cell Death may provide novel opportunities for targeted therapeutics. Thus, agents designed to selectively activate Death Receptor pathways may enhance the efficacy of conventional therapies and may even overcome some forms of cancer resistance.
-
Death Receptor Signaling in Cancer Therapy
Current Medicinal Chemistry-Anti-Cancer Agents, 2003Co-Authors: Simone Fulda, Klaus-michael DebatinAbstract:Apoptosis, the cell's intrinsic Death program, is a key regulator of tissue homeostasis. An imbalance between cell Death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies, such as chemotherapy, gamma-irradiation or ligation of Death Receptors is predominantly mediated by triggering apoptosis in target cells. Death Receptor signaling pathways have been implied to contribute to the efficacy of cancer therapy. Failure to undergo apoptosis in response to anticancer therapy may lead to resistance. Understanding the molecular events that regulate apoptosis induced by anticancer therapy and how cancer cells evade apoptosis may provide new opportunities for drug development. Thus, novel strategies targeting tumor cell resistance will be based on insights into the molecular mechanisms of cell Death.
-
sensitization for Death Receptor or drug induced apoptosis by re expression of caspase 8 through demethylation or gene transfer
Oncogene, 2001Co-Authors: Simone Fulda, Martin U Kufer, Eric P Meyer, Frans Van Valen, Barbara Dockhorndworniczak, Klaus-michael DebatinAbstract:Sensitization for Death Receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer
Zhigang Kang - One of the best experts on this subject based on the ideXlab platform.
-
caspase 8 expression is predictive of tumour response to Death Receptor 5 agonist antibody in ewing s sarcoma
British Journal of Cancer, 2015Co-Authors: Zhigang Kang, Seth D Goldstein, Paul S Meltzer, David M Loeb, Liang CaoAbstract:Despite good initial response to chemotherapy, 30% of Ewing’s sarcoma (EWS) patients with localised tumours develop recurrent disease, associated with poor prognosis. The aim of this study was to address this challenge by conducting preclinical evaluation of a Death Receptor targeted agent in vitro and in vivo, and by identifying predictive biomarkers. Cell viability assays, drug dose responses, immunoblots, rescue with gene transfer, mice tumour models, and statistical comparisons of tumour growth and Kaplan–Meier survival curves. This study shows that many EWS cell lines are selectively sensitive to a Death Receptor DR5 antibody and are more resistant to a DR4 antibody. Preclinical evaluation of these cell lines indicates their sensitivity to human DR5 agonist antibody conatumumab in vitro, which induces rapid activation of caspase-8 and apoptosis. We also found that sensitivity to conatumumab correlates with expression of caspase-8. Furthermore, the catalytic activity of caspase-8 is both necessary and sufficient to confer this sensitivity. In vivo, conatumumab is active against an EWS cell line and a patient-derived xenograft with higher caspase-8 expression, but is not effective against another with lower caspase-8 expression. These studies suggest the potential of conatumumab as a therapeutic agent against EWS and caspase-8 as a predictive biomarker for sensitivity.
Simone Fulda - One of the best experts on this subject based on the ideXlab platform.
-
Harnessing Death Receptor Signaling for Cancer Treatment
Cell Death Signaling in Cancer Biology and Treatment, 2012Co-Authors: Simone FuldaAbstract:Apoptosis, the cell’s intrinsic cell Death program, is a key regulator of tissue homeostasis. Accordingly, tilting the balance between cell Death on one side and cell proliferation on the other side toward survival promotes tumor formation. The Death Receptor (extrinsic) pathway represents one of the major apoptosis signaling cascades, which links exogenous stimuli via transmembrane surface Receptors to the intracellular signaling machinery that mediates and executes the Death signal. Since defects in Death Receptor signaling can confer resistance to apoptosis, a better understanding of the regulation of the signaling events and their perturbation in human cancers may lead to the identification of new molecular targets that can be exploited for therapeutic purposes. This strategy is expected to open new perspectives to target the Death Receptor pathway for cancer therapy.
-
Exploiting Death Receptor signaling pathways for tumor therapy
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2004Co-Authors: Simone Fulda, Klaus-michael DebatinAbstract:Apoptosis or programmed cell Death is a key regulator of physiological growth control and regulation of tissue homeostasis. Tipping the balance between cell Death and proliferation in favor of cell survival may result in tumor formation. Moreover, current cancer therapies, e.g. chemotherapy, gamma-irradiation, immunotherapy or suicide gene therapy, primarily exert their antitumor effect by triggering an evolutionary conserved apoptosis program in cancer cells. For example, Death Receptor signaling has been implied to contribute to the efficacy of cancer therapy. Thus, failure to undergo apoptosis in response to anticancer therapy because of defects in Death Receptor pathways may result in resistance. Further insights into the mechanisms regulating apoptosis in response to anticancer therapy and how cancer cells evade cell Death may provide novel opportunities for targeted therapeutics. Thus, agents designed to selectively activate Death Receptor pathways may enhance the efficacy of conventional therapies and may even overcome some forms of cancer resistance.
-
Death Receptor Signaling in Cancer Therapy
Current Medicinal Chemistry-Anti-Cancer Agents, 2003Co-Authors: Simone Fulda, Klaus-michael DebatinAbstract:Apoptosis, the cell's intrinsic Death program, is a key regulator of tissue homeostasis. An imbalance between cell Death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies, such as chemotherapy, gamma-irradiation or ligation of Death Receptors is predominantly mediated by triggering apoptosis in target cells. Death Receptor signaling pathways have been implied to contribute to the efficacy of cancer therapy. Failure to undergo apoptosis in response to anticancer therapy may lead to resistance. Understanding the molecular events that regulate apoptosis induced by anticancer therapy and how cancer cells evade apoptosis may provide new opportunities for drug development. Thus, novel strategies targeting tumor cell resistance will be based on insights into the molecular mechanisms of cell Death.
-
sensitization for Death Receptor or drug induced apoptosis by re expression of caspase 8 through demethylation or gene transfer
Oncogene, 2001Co-Authors: Simone Fulda, Martin U Kufer, Eric P Meyer, Frans Van Valen, Barbara Dockhorndworniczak, Klaus-michael DebatinAbstract:Sensitization for Death Receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer
