School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Clin Cancer Res. 2019 Feb 15;25(4):1415-1429. doi: 10.1158/1078-0432.CCR-18-1232. Epub 2018 Nov 16.
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.
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.
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 . 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.
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.
尼氯硝唑是一种获得美国食品药品监督管理局(FDA)批准的驱虫药物,已被鉴定为一种有效的 Wnt 抑制剂,可抑制肿瘤生长和癌症干细胞样细胞(CSC)群体。然而,其潜在的分子机制仍知之甚少。本研究旨在探讨尼氯硝唑通过抑制 Wnt 如何优先靶向 CSCs。
在公共数据库、人结直肠癌细胞、结直肠癌细胞异种移植和氧化偶氮甲烷/葡聚糖硫酸钠(AOM/DSS)诱导的结直肠癌细胞模型中,研究了尼氯硝唑抑制 CSC 的机制作用。
尼氯硝唑抑制结直肠癌细胞中的 CSC 群体及其自我更新活性,这种 CSC 靶向作用导致肿瘤起始潜力的不可逆破坏。从机制上讲,尼氯硝唑下调 Wnt 通路的多个信号成分,特别是淋巴增强因子结合蛋白 1(LEF1)的表达,这对于调节干细胞特性至关重要。随后,我们确定双皮质样激酶 1(DCLK1-B)是 LEF1 的靶标,并在上皮性结直肠癌细胞中上调癌症干细胞特性。我们首先记录到尼氯硝唑通过阻断 LEF1 与 DCLK1-B 启动子的结合来阻断 DCLK1-B 的转录。DCLK1-B 的缺失会损害癌症干细胞特性,导致存活能力降低和凋亡增加,从而使结直肠癌细胞对放化疗更加敏感。
尼氯硝唑通过破坏 LEF1/DCLK1-B 轴消除了癌症干细胞特性,并对结直肠癌细胞的起始、进展和耐药性产生了治疗效果。这些发现为将尼氯硝唑的临床评估扩大到结直肠癌治疗提供了临床前依据。