Therapeutic targeting of CBP/β-catenin signaling reduces cancer stem-like population and synergistically suppresses growth of EBV-positive nasopharyngeal carcinoma cells with cisplatin

King Chi Chan, Lai Sheung Chan, Joseph Chok Yan Ip, Carman Lo, Timothy Tak Chun Yip, Roger Kai Cheong Ngan, Ricky N S WONG, Kwok Wai Lo, Wai Tong Ng, Anne Wing Mui Lee, George Sai Wah Tsao, Michael Kahn, Maria Li Lung, Nai Ki MAK*

*Corresponding author for this work

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Abstract

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy prevalent in southern China. Presence of treatment-resistant cancer stem cells (CSC) may associate with tumor relapse and metastasis in NPC. ICG-001 is a specific CBP/β-catenin antagonist that can block CBP/β-catenin-mediated transcription of stem cell associated genes and enhance p300/β-catenin-mediated transcription, thereby reducing the CSC-like population via forced differentiation. In this study, we aimed to evaluate the effect of ICG-001 on the CSC-like population, and the combination effect of ICG-001 with cisplatin in the C666-1 EBV-positive NPC cells. Results showed that ICG-001 inhibited C666-1 cell growth and reduced expression of CSC-associated proteins with altered expression of epithelial-mesenchymal transition (EMT) markers. ICG-001 also inhibited C666-1 tumor sphere formation, accompanied with reduced SOX2 hi /CD44 hi CSC-like population. ICG-001 was also found to restore the expression of a tumor suppressive microRNA-145 (miR-145). Ectopic expression of miR-145 effectively repressed SOX2 protein expression and inhibited tumor sphere formation. Combination of ICG-001 with cisplatin synergistically suppressed in vitro growth of C666-1 cells and significantly suppressed growth of NPC xenografts. These results suggested that therapeutically targeting of the CBP/β-catenin signaling pathway with ICG-001 can effectively reduce the CSC-like population and combination with cisplatin can effectively suppress the growth of NPC.

Original languageEnglish
Article number9979
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 21 Apr 2015

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