Nobiletin inhibits invasion via inhibiting AKT/GSK3β/β-catenin signaling pathway in Slug-expressing glioma cells

Zhang,Xiang; Zheng,Kebin; Li,Chunhui; Zhao,Yonghui; Li,Heyang; Liu,Xuguang; Long,Yinbo; Yao,Junchao

doi:10.3892/or.2017.5522

Nobiletin inhibits invasion via inhibiting AKT/GSK3β/β-catenin signaling pathway in Slug-expressing glioma cells

Authors:
- Xiang Zhang
- Kebin Zheng
- Chunhui Li
- Yonghui Zhao
- Heyang Li
- Xuguang Liu
- Yinbo Long
- Junchao Yao
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Affiliations: Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China, Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
Published online on: March 23, 2017 https://doi.org/10.3892/or.2017.5522
Pages: 2847-2856

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Abstract

Epithelial-mesenchymal transition (EMT) is a pivotal event in tumor progression during which cancer cells undergo dramatic changes acquiring highly invasive properties. In this study, we found that nobiletin, a polymethoxylated flavone, suppressed migration and invasion in both U87 and U251 glioma cells. Expression of epithelial markers (E-cadherin and occludin) was upregulated; mesenchymal markers (N-cadherin, fibronectin) and the transcriptional factor Slug were downregulated after nobiletin treatment. Transforming growth factor β (TGF-β) was applied to stimulate EMT and the results showed that nobiletin not only influenced basal level cell migration but also prevented TGF-β-triggered migration and EMT, with the AKT/GSK3β/β-catenin signaling pathway greatly involved. Furthermore, nobiletin remarkably diminished TGF-β-induced β-catenin nuclear translocation and the binding to the Slug promoter. It is worth noting that nobiletin almost blocked invasion in Slug-expressing U87 and U251 cells, and only exhibiting faint effect on non-Slug-expressing U343 glioma cells. Reinforced Slug expression in U343 cells by transfecting Slug plasmid was significantly attenuated by nobiletin, demonstrating the essential role of Slug in the anti-metastasis effect of nobiletin. Nobiletin repressed tumor growth in vivo and abrogated EMT in nude mice bearing U87-Luc xenografts, as demonstrated by Xenogen IVIS imaging and immunohistochemistry assay. Our findings suggested that nobiletin might have a great potential for treating glioblastoma.

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