Journal article
Activation of NF-κB following detachment delays apoptosis in intestinal epithelial cells
Oncogene, v 24(43), pp 6482-6491
29 Sep 2005
PMID: 16007176
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
We reported earlier that IL-1β, an NF-κB-regulated cytokine, was made by intestinal epithelial cells during detachment-induced apoptosis (anoikis) and that IL-1 was antiapoptotic for detached cells. Since surviving anoikis is a prerequisite for cancer progression and metastases, we are further exploring the link between anoikis and cytokines. Here we determined that multiple genes are expressed following detachment including a number of NF-κB-regulated products and therefore aimed to determine whetherNF- κB signalling plays any role in regulating apoptosis. Using Western blotting, we detected that IκBα becomes phosphorylated immediately following detachment and that levels of phospho-IκBα peaked within 20 min. Phosphorylation of IκBα was followed by Rel A (p65) nuclear translocation. Increased NF-κB activity following detachment was confirmed using the detection of NF-κB-promoted luciferase gene expression delivered by adenovirus infection. Infection of cells with adenovirus expressing a super-repressor IκBα protein and pharmacological inhibitors of NF-κB resulted in the failure to phosphorylate IκBα, a more rapid activation of caspases and earlier apoptosis. We also detected that IκB kinase α (IKKα) and not IKKβ became phosphorylated following detachment. Since IKKα is activated by NF-κB-inducing kinase (NIK), we overexpressed native NIK using an adenovirus vector that resulted in enhanced phospho-IκBα and nuclear p65 in detached cells compared to control detached cells but did not result in a significantly greater number of cells surviving to 24 h. We conclude that detachment directly activates NF-κB, which, in addition to launching an inflammatory cytokine wave, contributes to a delay in apoptosis in intestinal epithelial cells.
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Details
- Title
- Activation of NF-κB following detachment delays apoptosis in intestinal epithelial cells
- Creators
- Sen Rong Yan - Department of Pediatrics, Dalhousie University, Halifax, NS, Canada B3H4R2Robbie Randle Joseph - Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada B3H4R2Kirill Rosen - Department of Pediatrics, Dalhousie University, Halifax, NS, Canada B3H4R2Mauricio J Reginato - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USAAmanda Jackson - Aventis Pharmaceuticals, Cambridge, MA, USANorman Allaire - Aventis Pharmaceuticals, Cambridge, MA, USAJoan S Brugge - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USAChristian Jobin - Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7080, USAAndrew W Stadnyk - Department of Pediatrics, Dalhousie University, Halifax, NS, Canada B3H4R2
- Publication Details
- Oncogene, v 24(43), pp 6482-6491
- Publisher
- Springer Nature
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000232204100002
- Scopus ID
- 2-s2.0-26944491533
- Other Identifier
- 991014877716504721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Genetics & Heredity
- Oncology