Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/β-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia

• Published in: Clinical cancer research Vol. 23; no. 3; pp. 789 - 803
• Main Authors: Jin, Bei, Wang, Chengyan, Li, Juan, Du, Xin, Ding, Ke, Pan, Jingxuan
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.02.2017
• Subjects: Animals; Anthelmintic agents; Anthelmintics - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; beta Catenin - metabolism; Cancer; CD34 antigen; Cell Self Renewal - drug effects; Cell self-renewal; Chromatin; Chromatin Immunoprecipitation; Chronic myeloid leukemia; Disease resistance; Drug Resistance, Neoplasm; Experimental design; Feedback loops; Feedback, Physiological - drug effects; Forkhead Box Protein M1 - metabolism; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Gene Expression Regulation, Leukemic; Graft Survival; Heterografts; Humans; Immunoprecipitation; Interleukin Receptor Common gamma Subunit - deficiency; K562 Cells; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Myeloid leukemia; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - drug effects; NF-κB protein; Niclosamide; Niclosamide - pharmacology; Nuclear transport; Positive feedback; Promoter Regions, Genetic; Protein Interaction Mapping; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Regulatory mechanisms (biology); RNA Interference; RNA, Small Interfering - genetics; Stem cell transplantation; Stem cells; Survival; Transcription; Transcription Factor RelA - metabolism; Translocation; Tyrosine; β-Catenin
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-0226

Purpose: 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. Experimental Design: 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.