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Statements

Subject Item
n2:RIV%2F68378050%3A_____%2F13%3A00422989%21RIV14-GA0-68378050
rdf:type
n9:Vysledek skos:Concept
dcterms:description
Tumour necrosis factor (TNF) related apoptosis inducing ligand (TRAIL), a membrane-bound ligand from the TNF family, has attracted significant attention due to its rather specific and effective ability to induce apoptotic death in various types of cancer cells via binding to and activating its pro-apoptotic death receptors. However, a significant number of primary cancer cells often develop resistance to TRAIL treatment, and the signalling platform behind this phenomenon is not fully understood. Upon blocking endosomal acidification by the vacuolar ATPase (V-ATPase) inhibitors bafilomycin A1 (BafA1) or concanamycin A, we observed a significantly reduced initial sensitivity of several, mainly colorectal, tumour cell lines to TRAIL-induced apoptosis. In cells pretreated with these inhibitors, the TRAIL-induced processing of caspase-8 and the aggregation and trafficking of the TRAIL receptor complexes were temporarily attenuated. Nuclear factor B or mitogen activated protein/stress kinase signalling from the activated TRAIL receptors remained unchanged, and neither possible lysosomal permeabilization nor acid sphingomyelinase was involved in this process. The cell surface expression of TRAIL receptors and their TRAIL-induced internalization were not affected by V-ATPase inhibitors. The inhibitory effect of BafA1, however, was blunted by knockdown of the caspase-8 inhibitor cFLIP. Altogether, the data obtained provide the first evidence that endosomal acidification could represent an important regulatory node in the proximal part of TRAIL-induced pro-apoptotic signalling. Tumour necrosis factor (TNF) related apoptosis inducing ligand (TRAIL), a membrane-bound ligand from the TNF family, has attracted significant attention due to its rather specific and effective ability to induce apoptotic death in various types of cancer cells via binding to and activating its pro-apoptotic death receptors. However, a significant number of primary cancer cells often develop resistance to TRAIL treatment, and the signalling platform behind this phenomenon is not fully understood. Upon blocking endosomal acidification by the vacuolar ATPase (V-ATPase) inhibitors bafilomycin A1 (BafA1) or concanamycin A, we observed a significantly reduced initial sensitivity of several, mainly colorectal, tumour cell lines to TRAIL-induced apoptosis. In cells pretreated with these inhibitors, the TRAIL-induced processing of caspase-8 and the aggregation and trafficking of the TRAIL receptor complexes were temporarily attenuated. Nuclear factor B or mitogen activated protein/stress kinase signalling from the activated TRAIL receptors remained unchanged, and neither possible lysosomal permeabilization nor acid sphingomyelinase was involved in this process. The cell surface expression of TRAIL receptors and their TRAIL-induced internalization were not affected by V-ATPase inhibitors. The inhibitory effect of BafA1, however, was blunted by knockdown of the caspase-8 inhibitor cFLIP. Altogether, the data obtained provide the first evidence that endosomal acidification could represent an important regulatory node in the proximal part of TRAIL-induced pro-apoptotic signalling.
dcterms:title
Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes
skos:prefLabel
Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes
skos:notation
RIV/68378050:_____/13:00422989!RIV14-GA0-68378050
n9:predkladatel
n10:ico%3A68378050
n3:aktivita
n7:V n7:P n7:I
n3:aktivity
I, P(1M0506), P(GAP301/10/1971), P(GAP301/11/1730), V
n3:cisloPeriodika
14
n3:dodaniDat
n13:2014
n3:domaciTvurceVysledku
n5:7103131 n5:9022643 n5:9013431 n5:6099017 n5:4290798 n5:7688857 n5:9437053
n3:druhVysledku
n15:J
n3:duvernostUdaju
n19:S
n3:entitaPredkladatele
n18:predkladatel
n3:idSjednocenehoVysledku
80214
n3:idVysledku
RIV/68378050:_____/13:00422989
n3:jazykVysledku
n14:eng
n3:klicovaSlova
acidification; apoptosis; caspase-8; TRAIL; V-ATPase
n3:klicoveSlovo
n4:acidification n4:apoptosis n4:V-ATPase n4:caspase-8 n4:TRAIL
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[AC11E7F5A2C5]
n3:nazevZdroje
FEBS Journal
n3:obor
n16:EB
n3:pocetDomacichTvurcuVysledku
7
n3:pocetTvurcuVysledku
10
n3:projekt
n11:GAP301%2F10%2F1971 n11:GAP301%2F11%2F1730 n11:1M0506
n3:rokUplatneniVysledku
n13:2013
n3:svazekPeriodika
280
n3:tvurceVysledku
Vaculová, Alena Klíma, Martin Jelínková, Iva Slavík, J. Hradilová, Naďa Bražina, Jan Švadlenka, Jan Anděra, Ladislav Koc, Michal Horová, Vladimíra
n3:wos
000327128700023
s:issn
1742-464X
s:numberOfPages
15
n17:doi
10.1111/febs.12347