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 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

doi:10.1038/srep09979

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

Sci Rep. 2015 Apr 21:5:9979. doi: 10.1038/srep09979.

Authors

Affiliations

¹ Department of Biology, Hong Kong Baptist University, P.R., China.
² Department of Clinical Oncology, University of Hong Kong, P.R., China.
³ Department of Anatomical and Cellular Pathology and State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, P.R., China.
⁴ 1] Department of Clinical Oncology, Queen Elizabeth Hospital Hong Kong, P.R., China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China.
⁵ 1] Department of Biology, Hong Kong Baptist University, P.R., China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China.
⁶ 1] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China [2] Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, P.R., China.
⁷ 1] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China [2] Department of Anatomy, University of Hong Kong, P.R., China.
⁸ Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ 1] Department of Clinical Oncology, University of Hong Kong, P.R., China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / therapeutic use
Antineoplastic Agents / toxicity*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Bridged Bicyclo Compounds, Heterocyclic / toxicity
Carcinoma
Cell Line, Tumor
Cell Proliferation / drug effects*
Cisplatin / therapeutic use
Cisplatin / 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
Nasopharyngeal Neoplasms / pathology
Nasopharyngeal Neoplasms / virology
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Pyrimidinones / therapeutic use
Pyrimidinones / toxicity
RNA Interference
RNA, Small Interfering / metabolism
SOXB1 Transcription Factors / antagonists & inhibitors
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Signal Transduction / drug effects*
Transplantation, Heterologous
beta Catenin / metabolism*
p300-CBP Transcription Factors / antagonists & inhibitors
p300-CBP Transcription Factors / metabolism*

Substances

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