title: The NF-kappaB pathway mediates fenretinide-induced apoptosis in SH-SY5Y neuroblastoma cells.
abstract: Fenretinide induces apoptosis in SH-SY5Y neuroblastoma cells via a signaling pathway involving the production of reactive oxygen species (ROS), 12-lipoxygenase activity and the induction of the GADD153 transcription factor. NF-kappa B is a key element of many cell signaling pathways and adopts a pro- or anti-apoptotic role in different cell types. Studies have suggested that NF-kappa B may play a pro-apoptotic role in SH-SY5Y cells, and in other cell types NF-kappa B activation may be linked to lipoxygenase activity. The aim of this study was to test the hypothesis that NF-kappa B activity mediates fenretinide-induced apoptosis in SH-SY5Y neuroblastoma cells. Using a dominant-negative construct for Ikappa Balpha stably transfected into SH-SY5Y cells, we show that apoptosis, but not the induction of ROS, in response to fenretinide was blocked by abrogation of NF-kappa B activity. In parental SH-SY5Y cells, fenretinide induced NF-kappa B activity and Ikappa Balpha phosphorylation. These results suggest that NF-kappa B activity links fenretinide-induced ROS to the induction of apoptosis in SH-SH5Y cells, and may be a target for the future development of drugs for neuroblastoma therapy.
authors.affiliation: Northern Institute for Cancer Research and School of Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Q D Campbell
authors.initials: QD
authors.lastname: Hewson
authors.forename: P E
authors.initials: PE
authors.lastname: Lovat
authors.forename: M
authors.initials: M
authors.lastname: Corazzari
authors.forename: J B
authors.initials: JB
authors.lastname: Catterall
authors.forename: C P F
authors.initials: CP
authors.lastname: Redfern
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D017313:Fenretinide / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009447:Neuroblastoma; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D017382:Reactive Oxygen Species; D000072000:NF-KappaB Inhibitor alpha; D017313:Fenretinide