Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5509412 | Cellular Signalling | 2016 | 11 Pages |
Abstract
In TGFβ-responsive Panc1 and Colo357 cells, TGFβ1 reduced total and plasma membrane-associated levels of TRAIL-R1 but not those of TRAIL-R2. Consistent with the known predominant role of TRAIL-R1 in TRAIL-mediated signaling in PDAC, TGFβ1 inhibited TRAIL-induced DISC formation and apoptosis as well as phosphorylation of MAPKs and IκBα. Similarly, it also reduced signaling of TRAIL-R1 following its specific activation with an agonistic antibody. In contrast, specific TRAIL-R2 signaling remained unchanged. The TGFβ1 effect on TRAIL-R1 expression was mimicked by ectopic expression of a kinase-active version of the TGFβ type I receptor ALK5 (ALK5-T204D) but not by ALK5 double mutant lacking the ability to phosphorylate Smad proteins (RImL45-T204D). Moreover, TGFβ regulation of TRAIL-R1 was absent in two PDAC cell lines lacking the Smad4 gene DPC4 and siRNA-mediated silencing of Smad4 in Smad4-positive Panc1 cells abolished the TGFβ-mediated decrease in TRAIL-R1 expression, together showing that ALK5/Smad4 signaling is crucial for TGFβ regulation of TRAIL-R1 expression. Our results suggest a novel tumor-promoting function of TGFβ1. By downregulating TRAIL-R1, TGFβ1 may not only promote tumor escape from immune surveillance but also negatively impact on TRAIL- or TRAIL-R1-based therapy regimens for treatment of PDAC.
Keywords
EGFJnkMFIMcl-1ERKactivin receptor-like kinase 5DISCFADDLexABcl-xLFLIPALK5FLICE-like inhibitory proteinc-Jun N-terminal kinaseepidermal growth factorB-cell lymphoma-extra largeMyeloid cell leukemia 1death inducing signaling complexMAPAFas-associated protein with death domainextracellular signal-regulated kinase
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Authors
David I. Radke, Hendrik Ungefroren, Ole Helm, Susann Voigt, Gökhan Alp, Hendrik Braun, Sebastian Hübner, Janine Dilchert, Susanne Sebens, Dieter Adam, Holger Kalthoff, Anna Trauzold,