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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Niclosamide is an FDA-approved drug known to inhibit Wnt signaling and suppress cancer stem-like cell (CSC) populations.
• The precise molecular mechanisms by which niclosamide targets CSCs and inhibits tumor growth are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying niclosamide's preferential targeting of CSCs in colorectal cancer.
• To elucidate how Wnt inhibition by niclosamide impacts CSC self-renewal and tumor-initiating potential.

Main Methods:

• Utilized public databases, human colorectal cancer cell lines, xenografts, and an AOM/DSS-induced colorectal cancer model.
• Examined the effects of niclosamide on Wnt pathway components, specifically LEF1 and DCLK1-B expression and function.
• Assessed the impact of niclosamide and DCLK1-B depletion on CSC self-renewal, tumor initiation, apoptosis, and chemosensitization.

Main Results:

• Niclosamide effectively suppressed CSC populations and their self-renewal capabilities in colorectal cancer cells, leading to irreversible loss of tumor-initiating potential in vivo.
• Niclosamide downregulated Wnt pathway signaling by inhibiting lymphoid enhancer-binding factor 1 (LEF1) expression, a key regulator of stemness.
• Identified DCLK1-B as a downstream target of LEF1; niclosamide blocked DCLK1-B transcription by preventing LEF1 binding to its promoter, impairing cancer stemness.

Conclusions:

• Disruption of the LEF1/DCLK1-B axis by niclosamide is a key mechanism for eradicating cancer stemness and achieving therapeutic effects in colorectal cancer.
• Niclosamide demonstrates preclinical efficacy in targeting colorectal cancer initiation, progression, and therapeutic resistance.
• These findings support further clinical evaluation of niclosamide for colorectal cancer treatment.