Journal
THERANOSTICS
Volume 7, Issue 7, Pages 2134-2149Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.17665
Keywords
nasopharyngeal carcinoma; beta-catenin nuclear translocation; CGP57380; poor prognosis; radiation-induced apoptosis
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Funding
- National Natural Science Foundations of China [81071820, 81272566, 81472773]
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Nuclear localization of beta-catenin is essential for the progression of various human cancers via transcriptional upregulation of downstream genes. The MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis has been reported to activate Wnt/beta-catenin signaling, and CGP57380, an inhibitor of MNK kinases, inhibits the proliferation of multiple cancers. In this study, we showed that beta-catenin signaling (including beta-catenin, cyclin D1, c-Myc, and MMP-7) and p-eIF4E expression were elevated in nasopharyngeal carcinoma (NPC) compared with non-cancerous nasopharyngeal epithelial tissues, and was associated with clinical characteristics of NPC patients. Lymph node metastasis, gender, aberrant beta-catenin expression, and elevated levels of MMP-7 and cyclin D1 were independent prognostic factors. Significantly, expression of p-eIF4E was positively correlated with beta-catenin, and targeting the MNK-eIF4E axis with CGP57380 downregulated beta-catenin in the nucleus, which in turn decreased proliferation, cell cycle progression, migration, invasion, and metastasis of NPC in vitro and in vivo. CGP57380 also potentiated radiation-induced apoptosis in NPC. Moreover, CGP57380 upregulated beta-catenin in the cytoplasm thus blocking epithelial-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. Mechanistically, inhibition of beta-catenin nuclear translocation by CGP57380 was dependent on AKT activation. Notably, identification of the MNK/eIF4E/beta-catenin axis might provide a potential target for overcoming the poor prognosis mediated by beta-catenin in NPC.
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