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

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.

• Authors: King Chi Chan, Lai Sheung Chan, Joseph Chok Yan Ip, Carman Lo, Timothy Tak Chun Yip, Roger Kai Cheong Ngan, Ricky Ngok Shun Wong, Kwok Wai Lo, Wai Tong Ng, Anne Wing Mui Lee, George Sai Wah Tsao, Michael Kahn, Maria Li Lung, Nai Ki Mak
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 9979 (Apr 21 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 25897700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Hyaluronan Receptors
• ICG 001
• MIRN145 microRNA, human
• MicroRNAs
• Pyrimidinones
• RNA, Small Interfering
• SOX2 protein, human
• SOXB1 Transcription Factors
• beta Catenin
• p300-CBP Transcription Factors
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (therapeutic use, toxicity)
• Bridged Bicyclo Compounds, Heterocyclic (therapeutic use, toxicity)
• Carcinoma
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (therapeutic use, toxicity)
• Drug Synergism
• Epithelial-Mesenchymal Transition (drug effects)
• Herpesvirus 4, Human (isolation & purification)
• Humans
• Hyaluronan Receptors (metabolism)
• Mice
• Mice, Nude
• MicroRNAs (metabolism)
• Microscopy, Confocal
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms (drug therapy, pathology, virology)
• Neoplastic Stem Cells (cytology, drug effects, metabolism)
• Pyrimidinones (therapeutic use, toxicity)
• RNA Interference
• RNA, Small Interfering (metabolism)
• SOXB1 Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Transplantation, Heterologous
• beta Catenin (metabolism)
• p300-CBP Transcription Factors (antagonists & inhibitors, metabolism)