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Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells
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 apopt...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067531/ https://www.ncbi.nlm.nih.gov/pubmed/24675460 http://dx.doi.org/10.1038/cddis.2014.102 |
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author | Zhang, J-S Herreros-Vilanueva, M Koenig, A Deng, Z de Narvajas, A A-M Gomez, T S Meng, X Bujanda, L Ellenrieder, V Li, X K Kaufmann, S H Billadeau, D D |
author_facet | Zhang, J-S Herreros-Vilanueva, M Koenig, A Deng, Z de Narvajas, A A-M Gomez, T S Meng, X Bujanda, L Ellenrieder, V Li, X K Kaufmann, S H Billadeau, D D |
author_sort | Zhang, J-S |
collection | PubMed |
description | 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-3α or GSK-3β. In contrast, depletion of GSK-3β, but not GSK-3α, sensitized PDA cell lines to TNFα-induced cell death. Further experiments demonstrated that TNFα-stimulated IκBα phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3β-deficient MEFs. Nonetheless, inhibition of GSK-3β function in MEFs or PDA cell lines impaired the expression of the NF-κB target genes Bcl-xL and cIAP2, but not IκBα. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3β targeted to the nucleus but not GSK-3β targeted to the cytoplasm, suggesting that GSK-3β regulates NF-κB 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-3β overexpression and nuclear localization contribute to TNFα and TRAIL resistance via anti-apoptotic NF-κB 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. |
format | Online Article Text |
id | pubmed-4067531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-40675312014-06-24 Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells Zhang, J-S Herreros-Vilanueva, M Koenig, A Deng, Z de Narvajas, A A-M Gomez, T S Meng, X Bujanda, L Ellenrieder, V Li, X K Kaufmann, S H Billadeau, D D Cell Death Dis Original Article 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-3α or GSK-3β. In contrast, depletion of GSK-3β, but not GSK-3α, sensitized PDA cell lines to TNFα-induced cell death. Further experiments demonstrated that TNFα-stimulated IκBα phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3β-deficient MEFs. Nonetheless, inhibition of GSK-3β function in MEFs or PDA cell lines impaired the expression of the NF-κB target genes Bcl-xL and cIAP2, but not IκBα. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3β targeted to the nucleus but not GSK-3β targeted to the cytoplasm, suggesting that GSK-3β regulates NF-κB 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-3β overexpression and nuclear localization contribute to TNFα and TRAIL resistance via anti-apoptotic NF-κB 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. Nature Publishing Group 2014-03 2014-03-27 /pmc/articles/PMC4067531/ /pubmed/24675460 http://dx.doi.org/10.1038/cddis.2014.102 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ 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/ |
spellingShingle | Original Article Zhang, J-S Herreros-Vilanueva, M Koenig, A Deng, Z de Narvajas, A A-M Gomez, T S Meng, X Bujanda, L Ellenrieder, V Li, X K Kaufmann, S H Billadeau, D D Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells |
title | Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or
TNFα induced apoptosis in pancreatic cancer cells |
title_full | Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or
TNFα induced apoptosis in pancreatic cancer cells |
title_fullStr | Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or
TNFα induced apoptosis in pancreatic cancer cells |
title_full_unstemmed | Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or
TNFα induced apoptosis in pancreatic cancer cells |
title_short | Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or
TNFα induced apoptosis in pancreatic cancer cells |
title_sort | differential activity of gsk-3 isoforms regulates nf-κb and trail- or
tnfα induced apoptosis in pancreatic cancer cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067531/ https://www.ncbi.nlm.nih.gov/pubmed/24675460 http://dx.doi.org/10.1038/cddis.2014.102 |
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