Nobiletin inhibits invasion via inhibiting AKT/GSK3ß/ß-catenin signaling pathway in Slug-expressing glioma cells.
Oncol Rep
; 37(5): 2847-2856, 2017 May.
Article
in En
| MEDLINE
| ID: mdl-28339056
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 ß (TGF-ß) was applied to stimulate EMT and the results showed that nobiletin not only influenced basal level cell migration but also prevented TGF-ß-triggered migration and EMT, with the AKT/GSK3ß/ß-catenin signaling pathway greatly involved. Furthermore, nobiletin remarkably diminished TGF-ß-induced ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
Flavones
/
Proto-Oncogene Proteins c-akt
/
Beta Catenin
/
Glycogen Synthase Kinase 3 beta
/
Snail Family Transcription Factors
/
Glioma
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Oncol Rep
Journal subject:
NEOPLASIAS
Year:
2017
Document type:
Article