title: 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.affiliation: Department of Biology, Hong Kong Baptist University, P.R., China.
authors.forename: King Chi
authors.initials: KC
authors.lastname: Chan
authors.affiliation: Department of Biology, Hong Kong Baptist University, P.R., China.
authors.forename: Lai Sheung
authors.initials: LS
authors.lastname: Chan
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, P.R., China.
authors.forename: Joseph Chok Yan
authors.initials: JC
authors.lastname: Ip
authors.affiliation: Department of Anatomical and Cellular Pathology and State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, P.R., China.
authors.forename: Carman
authors.initials: C
authors.lastname: Lo
authors.affiliation: 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.
authors.forename: Timothy Tak Chun
authors.initials: TT
authors.lastname: Yip
authors.affiliation: 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.
authors.forename: Roger Kai Cheong
authors.initials: RK
authors.lastname: Ngan
authors.affiliation: 1] Department of Biology, Hong Kong Baptist University, P.R., China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China.
authors.forename: Ricky Ngok Shun
authors.initials: RN
authors.lastname: Wong
authors.affiliation: Department of Anatomical and Cellular Pathology and State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, P.R., China.
authors.forename: Kwok Wai
authors.initials: KW
authors.lastname: Lo
authors.affiliation: 1] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China [2] Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, P.R., China.
authors.forename: Wai Tong
authors.initials: WT
authors.lastname: Ng
authors.affiliation: 1] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China [2] Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, P.R., China.
authors.forename: Anne Wing Mui
authors.initials: AW
authors.lastname: Lee
authors.affiliation: 1] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China [2] Department of Anatomy, University of Hong Kong, P.R., China.
authors.forename: George Sai Wah
authors.initials: GS
authors.lastname: Tsao
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.affiliation: 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.
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
authors.affiliation: 1] Department of Biology, Hong Kong Baptist University, P.R., China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China.
authors.forename: Nai Ki
authors.initials: NK
authors.lastname: Mak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use / Q000633:toxicity; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity*; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D018613:Microscopy, Confocal; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011744:Pyrimidinones / Q000627:therapeutic use / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018960:Hyaluronan Receptors; C492448:ICG 001; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D011744:Pyrimidinones; D034741:RNA, Small Interfering; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051176:beta Catenin; D050880:p300-CBP Transcription Factors; D002945:Cisplatin