title: Regulation of the FOXO3a/Bim signaling pathway by 5,7-dihydroxy-8-nitrochrysin in MDA-MB-453 breast cancer cells.
abstract: We previously demonstrated that 5,7-dihydroxy-8-nitrochrysin (NOC), a novel synthetic chrysin analog, preferentially inhibits HER-2/neu-overexpressing MDA-MB-453 breast cancer cell growth by inducing apoptosis; however, the precise molecular mechanism was unclear. In this study, we demonstrated that NOC significantly induces apoptosis of MDA-MB-453 cells and that this is primarily mediated through a mitochondrial death cascade. This was presented as a loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9. NOC induces a significant increase in levels of the BH3-only protein Bim. Small interfering RNA-mediated knockdown of Bim markedly attenuated NOC-induced apoptosis. An upstream transcriptional regulator of Bim, forkhead box O3a transcription factor (FOXO3a), experienced a decrease in phosphorylation and nuclear translocation. Silencing of FOXO3a resulted in a marked attenuation in the expression of Bim, as well as protection against NOC-mediated apoptosis. Furthermore, NOC-induced activation and nuclear localization of FOXO3a was associated with reduced levels of Akt phosphorylation. These results suggest that NOC induces apoptosis in MDA-MB-453 human breast cancer cells via caspase activation and modulation of the Akt/FOXO3a pathway.
authors: Department of Oncology, First Affiliated Hospital of University of South China, Hengyang 421001;
authors: Xiao-Chun
authors: XC
authors: Zhao
authors: Xiao-Cheng
authors: XC
authors: Cao
authors: Fei
authors: F
authors: Liu
authors: Mei-Fang
authors: MF
authors: Quan
authors: Kai-Qun
authors: KQ
authors: Ren
authors: Jian-Guo
authors: JG
authors: Cao
keywords: 5,7-dihydroxy-8-nitrochrysin; Akt; Bim; breast cancer; chrysin; forkhead box O3a