Niclosamide Attenuates Colorectal Cancer Stemness by Inhibiting Wnt/LEF1/DCLK1 Axis

Abstract

Niclosamide, an FDA-approved anthelmintic drug, has been characterized as a potent Wnt inhibitor that can suppress tumor growth and cancer stem cell (CSC) populations. However, the underlying molecular mechanisms remain poorly understood. In this study, we examined how Wnt inhibition by niclosamide preferentially targets CSCs, based on public databases, human colorectal cancer (CRC) cells, CRC xenografts, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC model. 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 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. These findings provide a preclinical rationale to broaden the clinical evaluation of niclosamide for the treatment of CRC.