Hewson Q D Campbell, Lovat P E, Corazzari M, Catterall J B, Redfern C P F
Northern Institute for Cancer Research and School of Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
Apoptosis. 2005 May;10(3):493-8. doi: 10.1007/s10495-005-1878-z.
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.
芬维A胺通过一条涉及活性氧（ROS）生成、12-脂氧合酶活性以及GADD153转录因子诱导的信号通路，诱导SH-SY5Y神经母细胞瘤细胞凋亡。核因子-κB（NF-κB）是许多细胞信号通路的关键元件，在不同细胞类型中发挥促凋亡或抗凋亡作用。研究表明，NF-κB可能在SH-SY5Y细胞中发挥促凋亡作用，并且在其他细胞类型中，NF-κB激活可能与脂氧合酶活性有关。本研究的目的是验证NF-κB活性介导芬维A胺诱导SH-SY5Y神经母细胞瘤细胞凋亡这一假说。通过将一种针对IκBα的显性负性构建体稳定转染到SH-SY5Y细胞中，我们发现，NF-κB活性的消除可阻断芬维A胺诱导的凋亡，但不影响ROS的诱导。在亲代SH-SY5Y细胞中，芬维A胺诱导NF-κB活性及IκBα磷酸化。这些结果表明，NF-κB活性将芬维A胺诱导的ROS与SH-SY5Y细胞凋亡的诱导联系起来，并且可能是未来神经母细胞瘤治疗药物开发的一个靶点。
