Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness
- Authors
- Park, So-Yeon; Kim, Ji-Young; Choi, Jang-Hyun; Kim, Jee-Heun; Lee, Choong-Jae; Singh, Pomila; Sarkar, Shubhashish; Baek, Jeong-Heum; Nam, Jeong-Seok
- Issue Date
- 15-Feb-2019
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- CLINICAL CANCER RESEARCH, v.25, no.4, pp.1415 - 1429
- Journal Title
- CLINICAL CANCER RESEARCH
- Volume
- 25
- Number
- 4
- Start Page
- 1415
- End Page
- 1429
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/1841
- DOI
- 10.1158/1078-0432.CCR-18-1232
- ISSN
- 1078-0432
- 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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