TY - JOUR
T1 - NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer
AU - Geismann, Claudia
AU - Hauser, Charlotte
AU - Grohmann, Frauke
AU - Schneeweis, Christian
AU - Bölter, Nico
AU - Gundlach, Jan Paul
AU - Schneider, Günter
AU - Röcken, Christoph
AU - Meinhardt, Christian
AU - Schäfer, Heiner
AU - Schreiber, Stefan
AU - Arlt, Alexander
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/1
Y1 - 2023/1
N2 - The emergence of resistance to systemic therapies in pancreatic ductal adenocarcinoma (PDAC) is still a major obstacle in clinical practice. Both, constitutive and inducible NF-κB activity are known as key players in this context. To identify differentially expressed and TRAIL resistance mediating NF-κB target genes, TRAIL sensitive and resistant PDAC cell lines were analyzed by transcriptome assays. In this context, A20 was identified as an NF-κB/RelA inducible target gene. Translational PDAC tissue analysis confirmed the correlation of elevated A20 protein expression with activated RelA expression in PDAC patients. In in vitro experiments, an elevated A20 expression is accompanied by a specific resistance toward TRAIL-mediated apoptosis but not to chemotherapeutic-induced cell death. This TRAIL resistance was attributed to A20´s E3-ligase activity-mediating Zink finger domain. Furthermore, the ubiquitin-binding scaffold protein p62 was identified as indispensable for the TRAIL-mediated apoptosis-inducing pathway affected by A20. The results of this study identify A20 as a possible therapeutic target to affect resistance to TRAIL-induced apoptosis in PDAC cells.
AB - The emergence of resistance to systemic therapies in pancreatic ductal adenocarcinoma (PDAC) is still a major obstacle in clinical practice. Both, constitutive and inducible NF-κB activity are known as key players in this context. To identify differentially expressed and TRAIL resistance mediating NF-κB target genes, TRAIL sensitive and resistant PDAC cell lines were analyzed by transcriptome assays. In this context, A20 was identified as an NF-κB/RelA inducible target gene. Translational PDAC tissue analysis confirmed the correlation of elevated A20 protein expression with activated RelA expression in PDAC patients. In in vitro experiments, an elevated A20 expression is accompanied by a specific resistance toward TRAIL-mediated apoptosis but not to chemotherapeutic-induced cell death. This TRAIL resistance was attributed to A20´s E3-ligase activity-mediating Zink finger domain. Furthermore, the ubiquitin-binding scaffold protein p62 was identified as indispensable for the TRAIL-mediated apoptosis-inducing pathway affected by A20. The results of this study identify A20 as a possible therapeutic target to affect resistance to TRAIL-induced apoptosis in PDAC cells.
UR - http://www.scopus.com/inward/record.url?scp=85145431272&partnerID=8YFLogxK
U2 - 10.1038/s41419-022-05535-9
DO - 10.1038/s41419-022-05535-9
M3 - Article
C2 - 36596765
AN - SCOPUS:85145431272
SN - 2041-4889
VL - 14
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 1
M1 - 3
ER -
