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dc.contributor.authorNahacka, Zuzana
dc.contributor.authorSvadlenka, Jan
dc.contributor.authorPeterka, Martin
dc.contributor.authorKsandrova, Marie
dc.contributor.authorBenesova, Simona
dc.contributor.authorNeuzil, Jiri
dc.contributor.authorAndera, Ladislav
dc.date.accessioned2019-06-08T01:40:54Z
dc.date.available2019-06-08T01:40:54Z
dc.date.issued2018
dc.identifier.issn0167-4889
dc.identifier.doi10.1016/j.bbamcr.2017.12.006
dc.identifier.urihttp://hdl.handle.net/10072/376854
dc.description.abstractTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that can trigger apoptosis in many types of human cancer cells via engagement of its two pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). TRAIL can also activate several other signaling pathways such as activation of stress kinases, canonical NF-κB signaling and necroptosis. Though both receptors are ubiquitously expressed, their relative participation in TRAIL-induced signaling is still largely unknown. To analyze TRAIL receptor-specific signaling, we prepared Strep-tagged, trimerized variants of recombinant human TRAIL with high affinity for either DR4 or DR5 receptor. Using these receptor-specific ligands, we examined the contribution of individual pro-apoptotic receptors to TRAIL-induced signaling pathways. We found that in TRAIL-resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells, DISC formation and initial caspase-8 processing proceeds comparably via both DR4- and DR5-activated signaling. TRAIL-induced apoptosis, enhanced by the inhibitor of the Bcl-2 family ABT-737, or by the translation inhibitor homoharringtonine, proceeded in both cell lines predominantly via the DR5 receptor. ShRNA-mediated downregulation of DR4 or DR5 receptors in HT-29 cells also pointed to a stronger contribution of DR5 in TRAIL-induced apoptosis. In contrast to apoptosis, necroptotic signaling was activated similarly by both DR4- or DR5-specific ligands. Activation of auxiliary signaling pathways involving NF-κB or stress kinases proceeded under apoptotic conditions mainly in a DR5-dependent manner, while these signaling pathways were during necroptosis similarly activated by either of these ligands. Our study provides the first systematic insight into DR4 −/DR5-specific signaling in colorectal and pancreatic cancer cells.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.publisher.placeNetherlands
dc.relation.ispartofpagefrom522
dc.relation.ispartofpageto531
dc.relation.ispartofissue3
dc.relation.ispartofjournalBiochimica et Biophysica Acta - Molecular Cell Research
dc.relation.ispartofvolume1865
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchMedical microbiology not elsewhere classified
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3207
dc.subject.fieldofresearchcode320799
dc.titleTRAIL induces apoptosis but not necroptosis in colorectal and pancreatic cancer cells preferentially via the TRAIL-R2/DR5 receptor
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2018 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorNeuzil, Jiri


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