Regulation of the FOXO3a/Bim signaling pathway by 5,7-dihydroxy-8-nitrochrysin in MDA-MB-453 breast cancer cells

Zhao,Xiao-Chun; Cao,Xiao-Cheng; Liu,Fei; Quan,Mei-Fang; Ren,Kai-Qun; Cao,Jian-Guo

doi:10.3892/ol.2012.1077

Regulation of the FOXO3a/Bim signaling pathway by 5,7-dihydroxy-8-nitrochrysin in MDA-MB-453 breast cancer cells

Authors:
- Xiao-Chun Zhao
- Xiao-Cheng Cao
- Fei Liu
- Mei-Fang Quan
- Kai-Qun Ren
- Jian-Guo Cao
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Affiliations: Department of Oncology, First Affiliated Hospital of University of South China, Hengyang 421001, P.R. China, Laboratory of Medicine Engineering, Medical College, Hunan Normal University, Changsha 410013, P.R. China
Published online on: December 14, 2012 https://doi.org/10.3892/ol.2012.1077
Pages: 929-934

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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.

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