Theranostics 2017; 7(7):2134-2149. doi:10.7150/thno.17665
Suppression Of β-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma
1. Department of Pathology, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China;
2. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Nuclear localization of β-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/β-catenin signaling, and CGP57380, an inhibitor of MNK kinases, inhibits the proliferation of multiple cancers. In this study, we showed that β-catenin signaling (including β-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 β-catenin expression, and elevated levels of MMP-7 and cyclin D1 were independent prognostic factors. Significantly, expression of p-eIF4E was positively correlated with β-catenin, and targeting the MNK-eIF4E axis with CGP57380 downregulated β-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 β-catenin in the cytoplasm thus blocking epithelial-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. Mechanistically, inhibition of β-catenin nuclear translocation by CGP57380 was dependent on AKT activation. Notably, identification of the MNK/eIF4E/β-catenin axis might provide a potential target for overcoming the poor prognosis mediated by β-catenin in NPC.
Keywords: nasopharyngeal carcinoma, β-catenin nuclear translocation, CGP57380, poor prognosis, radiation-induced apoptosis.
Wang W, Wen Q, Luo J, Chu S, Chen L, Xu L, Zang H, Alnemah MM, Li J, Zhou J, Fan S. Suppression Of β-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma. Theranostics 2017; 7(7):2134-2149. doi:10.7150/thno.17665. Available from http://www.thno.org/v07p2134.htm