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Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

Clinical Cancer research : an official journal of the American Association for Cancer Research v.25 no.4 , 2019년, pp.1415 - 1429  
Park, So-Yeon (School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. ) ;  Kim, Ji-Young ( Laboratory Animal Resource Center, Gwangju Institute of Science and Technology, Gwnagju, Republic of Korea. ) ;  Choi, Jang-Hyun ( School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. ) ;  Kim, Jee-Heun ( School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. ) ;  Lee, Choong-Jae ( School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. ) ;  Singh, Pomila ( Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas. ) ;  Sarkar, Shubhashish ( Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas. ) ;  Baek, Jeong-Heum ( Division of Colon and Rectal Surgery, Department of Surgery, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea. ) ;  Nam, Jeong-Seok ( School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.)
Abstract

Purpose:Niclosamide, an FDA-approved anthelmintic drug, has been characterized as a potent Wnt inhibitor that can suppress tumor growth and cancer stem-like cell (CSC) populations. However, the underlying molecular mechanisms remain poorly understood. This study aimed to examine how Wnt inhibition by niclosamide preferentially targets CSCs.Experimental Design:The mechanistic role of niclosamide in CSC inhibition was examined in public databases, human colorectal cancer cells, colorectal cancer xenografts, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colorectal cancer model.Results:Niclosamide suppresses CSC populations and their self-renewal activities in colorectal cancer cells, and this CSC-targeting effect leads to irreversible disruption of tumor-initiating potential in vivo. Mechanistically, niclosamide downregulates multiple signaling components of the Wnt pathway, specifically lymphoid enhancer-binding factor 1 (LEF1) expression, which is critical for regulating stemness. Subsequently, we identified that the doublecortin-like kinase 1 (DCLK1)-B is a target of LEF1 and upregulates cancer stemness in colorectal cancer cells. We first documented that niclosamide blocks the transcription of DCLK1-B by interrupting the binding of LEF1 to DCLK1-B promoter. DCLK1-B depletion impairs cancer stemness resulting in reduced survival potential and increased apoptosis, thus sensitizing colorectal cancer to chemoradiation.Conclusions:Disruption of the LEF1/DCLK1-B axis by niclosamide eradicates cancer stemness and elicits therapeutic effects on colorectal cancer initiation, progression, and resistance. These findings provide a preclinical rationale to broaden the clinical evaluation of niclosamide for the treatment of colorectal cancer.

  

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