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

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. The current 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 (CRC) cells, CRC xenografts, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC model. Results: Niclosamide suppresses CSC populations and their self-renewal activities in CRC 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 kinase1 (DCLK1)-B is a target of LEF1 and upregulates cancer stemness in CRC 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 CRC to chemoradiation. Conclusions: Disruption of the LEF1/DCLK1-B axis by niclosamide eradicates cancer stemness and elicits therapeutic effects on CRC initiation, progression, and resistance. These findings provide a preclinical rationale to broaden the clinical evaluation of niclosamide for the treatment of CRC.

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