We are analyzing https://link.springer.com/article/10.1007/s00109-010-0619-0.

Title:
TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5 | Journal of Molecular Medicine
Description:
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF–κB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.
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article, google, scholar, cas, pubmed, trail, receptor, signaling, apoptosis, cells, tumor, cell, death, cancer, pancreatic, trauzold, ligand, biol, lee, necrosis, apoptosisinducing, trailr, factorrelated, kalthoff, activation, receptors, human, park, oncogene, privacy, cookies, content, journal, molecular, wajant, adenocarcinoma, access, walczak, roder, protein, data, information, publish, research, search, medicine, lemke, adam, related, antibodies,

Topics {✒️}

month download article/chapter death-inducing signaling complex anti-dr5/trail-r2 antibodies proapoptotic ligand apo2l/trail agonistic anti-dr4/trail-r1 trail-receptor-mediated apoptosis pancreatic tumor cells trail-mediated dr5-disc formation drug-induced apoptosis trail-induced apoptosis trail-receptor-specific antibodies related regulatory pathways dr5-specific fab fragments nf–κb activation side cytotoxic ligand trail p53 tumor suppressor apoptosis-mediating receptor fadd-binding death receptors related subjects full article pdf tumor-derived mutations pancreatic cancer cells molecular medicine aims molecular internal medicine pancreatic tumour cells pancreatic carcinoma cells privacy choices/manage cookies experimental cancer research apoptosis-controlling genes receptor-selective mutants ligand binding death receptor signaling agonistic-antibody treatment human genome sciences lexatumumab induce formation degli-esposti ma electronic supplementary material activate cell death death signaling vesicles apoptotic signaling pathways trigger apoptotic signaling analyzed cell viability alternatively spliced receptor pro-inflammatory signaling survival signaling leads dfg grants schu733/7-1 internal medicine ii killer/dr5 gene functional binding sites apoptosis signaling

Questions {❓}

Newsom-Davis T, Prieske S, Walczak H (2009) Is TRAIL the holy grail of cancer therapy?

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         description:Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF–κB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.
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