Inhibition of LEF1-mediated DCLK1 by niclosamide attenuates colorectal cancer stemness

So Yeon Park, Ji Young Kim, Jang Hyun Choi, Jee Heun Kim, Choong Jae Lee, Pomila Singh, Shubhashish Sarkar, Jeong Heum Baek, Jeong Seok Nam

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5 Scopus citations

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 azox-ymethane/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.

Original languageEnglish (US)
Pages (from-to)1415-1429
Number of pages15
JournalClinical Cancer Research
Volume25
Issue number4
DOIs
StatePublished - Feb 15 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Park, S. Y., Kim, J. Y., Choi, J. H., Kim, J. H., Lee, C. J., Singh, P., Sarkar, S., Baek, J. H., & Nam, J. S. (2019). Inhibition of LEF1-mediated DCLK1 by niclosamide attenuates colorectal cancer stemness. Clinical Cancer Research, 25(4), 1415-1429. https://doi.org/10.1158/1078-0432.CCR-18-1232