Nobiletin inhibits invasion via inhibiting AKT/GSK3β/β-catenin signaling pathway in Slug-expressing glioma cells.
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.
Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China.
Xiang
X
Zhang
Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China.
Kebin
K
Zheng
Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China.
Chunhui
C
Li
Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China.
Yonghui
Y
Zhao
Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China.
Heyang
H
Li
Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China.
Xuguang
X
Liu
Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China.
Yinbo
Y
Long
Department of Neurosurgery, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China.
Junchao
J
Yao
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D047309:Flavones / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
D047309:Flavones; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051176:beta Catenin; C008661:nobiletin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt