Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness
DC Field | Value | Language |
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dc.contributor.author | Park, So-Yeon | - |
dc.contributor.author | Kim, Ji-Young | - |
dc.contributor.author | Choi, Jang-Hyun | - |
dc.contributor.author | Kim, Jee-Heun | - |
dc.contributor.author | Lee, Choong-Jae | - |
dc.contributor.author | Singh, Pomila | - |
dc.contributor.author | Sarkar, Shubhashish | - |
dc.contributor.author | Baek, Jeong-Heum | - |
dc.contributor.author | Nam, Jeong-Seok | - |
dc.date.available | 2020-02-27T04:41:31Z | - |
dc.date.created | 2020-02-05 | - |
dc.date.issued | 2019-02-15 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/1841 | - |
dc.description.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. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | AMER ASSOC CANCER RESEARCH | - |
dc.relation.isPartOf | CLINICAL CANCER RESEARCH | - |
dc.subject | DRUG NICLOSAMIDE | - |
dc.subject | SELF-RENEWAL | - |
dc.subject | CELLS | - |
dc.subject | TUMOR | - |
dc.subject | TUMORIGENESIS | - |
dc.subject | MARKER | - |
dc.title | Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000458739900031 | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-18-1232 | - |
dc.identifier.bibliographicCitation | CLINICAL CANCER RESEARCH, v.25, no.4, pp.1415 - 1429 | - |
dc.identifier.scopusid | 2-s2.0-85061578725 | - |
dc.citation.endPage | 1429 | - |
dc.citation.startPage | 1415 | - |
dc.citation.title | CLINICAL CANCER RESEARCH | - |
dc.citation.volume | 25 | - |
dc.citation.number | 4 | - |
dc.contributor.affiliatedAuthor | Baek, Jeong-Heum | - |
dc.type.docType | Article | - |
dc.subject.keywordPlus | DRUG NICLOSAMIDE | - |
dc.subject.keywordPlus | SELF-RENEWAL | - |
dc.subject.keywordPlus | CELLS | - |
dc.subject.keywordPlus | TUMOR | - |
dc.subject.keywordPlus | TUMORIGENESIS | - |
dc.subject.keywordPlus | MARKER | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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