dc.contributor.author | Zhang, J.S. | |
dc.contributor.author | Herreros Villanueva, Marta | |
dc.contributor.author | Koenig, A. | |
dc.contributor.author | Deng, Z. | |
dc.contributor.author | M De Narvajas, A. A. | |
dc.contributor.author | Gómez, T. S. | |
dc.contributor.author | Meng, X. | |
dc.contributor.author | Bujanda Fernández de Pierola, Luis | |
dc.contributor.author | Ellenrieder, V. | |
dc.contributor.author | Li, X. K. | |
dc.contributor.author | Kaufmann, S. H. | |
dc.contributor.author | Billadeau, D. D. | |
dc.date.accessioned | 2016-02-18T12:38:29Z | |
dc.date.available | 2016-02-18T12:38:29Z | |
dc.date.issued | 2014-03 | |
dc.identifier.citation | Cell Death and Disease 5 : (2014) // Article ID e1142 | es |
dc.identifier.issn | 2041-4889 | |
dc.identifier.uri | http://hdl.handle.net/10810/17385 | |
dc.description.abstract | While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3 alpha or GSK-3 beta. In contrast, depletion of GSK-3 beta, but not GSK-3 alpha, sensitized PDA cell lines to TNF alpha-induced cell death. Further experiments demonstrated that TNF alpha-stimulated I kappa B alpha phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3 beta-deficient MEFs. Nonetheless, inhibition of GSK-3 beta function in MEFs or PDA cell lines impaired the expression of the NF-kappa B target genes Bcl-xL and cIAP2, but not I kappa B alpha. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3 beta targeted to the nucleus but not GSK-3 beta targeted to the cytoplasm, suggesting that GSK-3 beta regulates NF-kappa B function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3 beta overexpression and nuclear localization contribute to TNF alpha and TRAIL resistance via anti-apoptotic NF-kappa B genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA. | es |
dc.description.sponsorship | This work was supported, in part by the Mayo Clinic Pancreatic Cancer SPORE P50CA102701 (DDB), Mayo Clinic Prostate Cancer SPORE Developmental Project (J-SZ), American Cancer Society Institutional New Investigator Award (J-SZ), R01 CA69008 (SHK), funds from Universidad del Pais Vasco and CIBERehd (MHV) a Mildred-Scheel fellowship of German Cancer Society (VE and AK), and Reserve Talent of Universities Overseas Research Program of Heilongjiang (ZD). | es |
dc.language.iso | eng | es |
dc.publisher | Nature Publishing Group | es |
dc.rights | info:eu-repo/semantics/openAccess | es |
dc.subject | apoptosis | es |
dc.subject | GSK-3 | es |
dc.subject | NF-kappa B | es |
dc.subject | pancreatic cancer | es |
dc.subject | TNF alpha | es |
dc.subject | TRAIL | es |
dc.subject | glicogel-synthase kinase-3-beta | es |
dc.subject | tumor-necrosis-factor | es |
dc.subject | ductal adenocarcinoma | es |
dc.subject | funcional redundancy | es |
dc.subject | signaling pathways | es |
dc.subject | XIAP inhibitors | es |
dc.subject | kinase-activity | es |
dc.subject | in-vitro | es |
dc.subject | activation | es |
dc.subject | resistance | es |
dc.title | Differential activity of GSK-3 isoforms regulates NF-kappa B and TRAIL- or TNF alpha induced apoptosis in pancreatic cancer cells | es |
dc.type | info:eu-repo/semantics/article | es |
dc.rights.holder | Cell Death and Disease is an open-access journal
published by Nature Publishing Group. This work is
licensed under a Creative Commons Attribution-NonCommercial-
NoDerivs 3.0 Unported License. To view a copy of this license, visit
http://creativecommons.org/licenses/by-nc-nd/3.0/ | es |
dc.relation.publisherversion | http://www.nature.com/cddis/journal/v5/n3/full/cddis2014102a.html#abs | es |
dc.identifier.doi | 10.1038/cddis.2014.102 | |
dc.departamentoes | Medicina | es_ES |
dc.departamentoeu | Medikuntza | es_ES |
dc.subject.categoria | CELL BIOLOGY | |
dc.subject.categoria | ONCOLOGY | |
dc.subject.categoria | MEDICINE | |
dc.subject.categoria | IMMUNOLOGY AND MICROBIOLOGY | |
dc.subject.categoria | CELLULAR AND MOLECULAR NEUROSCIENCE | |