title: Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/β-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia.
abstract: OBJECTIVE
  Leukemia stem cells (LSC), which are insensitive to tyrosine kinase inhibitors (TKI), are an important source of TKI resistance and disease relapse in chronic myelogenous leukemia (CML). Obstacles to eradicating LSCs include limited understanding of the regulation network of LSCs. The current study aimed to examine the interplay between NF-κB and FOXM1/β-catenin, and the effect of its chemical intervention on CML LSCs.
  
  
  METHODS
  The interplay between NF-κB and FOXM1/β-catenin was analyzed by reciprocal coimmunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assay in CML cells. The effect of disturbing NF-κB and FOXM1/β-catenin by niclosamide on the self-renewal capacity and survival of LSCs was evaluated in vitro in human primary CML CD34+cells and in vivo in CML mice.
  
  
  RESULTS
  Reciprocal co-IP experiments showed physical interaction of p65 and FOXM1. p65 promoted transcription of FOXM1 gene. ChIP assay revealed recruitment of p65 on the promoter of FOXM1 gene. Conversely, FOXM1 and β-catenin positively regulated the nuclear translocation and transcriptional activity of NF-κB in CML cells. Niclosamide disrupted the positive feedback loop between NF-κB and FOXM1/β-catenin, thereby impairing the self-renewal capacity and survival of CML LSCs. Niclosamide decreased the long-term engraftment of human CML LSCs in NOD-SCID IL2Rγ chain-deficient (NOG) mice, and prolonged the survival of CML mice.
  
  
  CONCLUSIONS
  Interaction of p65 with FOXM1/β-catenin is critical in CML and its disruption by niclosamide eradicates LSCs. These findings may improve the understanding of a self-renewal regulatory mechanism of LSCs and offer a rationale-based approach to eliminate LSCs in CML. Clin Cancer Res; 23(3); 789-803. ©2016 AACR.
authors: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors: Bei
authors: B
authors: Jin
authors: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors: Chengyan
authors: C
authors: Wang
authors: Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Juan
authors: J
authors: Li
authors: Department of Hematology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China.
authors: Xin
authors: X
authors: Du
authors: Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors: Ke
authors: K
authors: Ding
authors: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. panjx2@mail.sysu.edu.cn.|Jinan University Institute of Tumor Pharmacology, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors: Jingxuan
authors: J
authors: Pan
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm; D025461:Feedback, Physiological / Q000187:drug effects; D000072278:Forkhead Box Protein M1 / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006085:Graft Survival; D064593:Heterografts; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009534:Niclosamide / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000871:Anthelmintics; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D051176:beta Catenin; D009534:Niclosamide; D016044:Fusion Proteins, bcr-abl