Nigericin, an antibiotic derived from Streptomyces hygroscopicus, which works by acting as an H+, K+, and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer cells and clarify the underlying mechanism. We exposed two colorectal cancer lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in colorectal cancer cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration, and invasion, and induce the apoptosis of colorectal cancer cells. Our results of Western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in colorectal cancer cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin–dependent signaling mechanism, we established the stably β-catenin overexpression colorectal cancer cells. Western blot, SuperTOPFlash luciferase reporter, and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anticancer effects on colorectal cancer cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in colorectal cancer progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin toward cancer cells, and suggest possible clinical application in colorectal cancer. Mol Cancer Ther; 17(5); 952–65. ©2018 AACR.

中文翻译：

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尼日利亚菌素通过抑制Wnt/β-catenin信号通路对人结直肠癌细胞发挥抗癌作用

Nigericin 是一种源自吸水链霉菌的抗生素，通过充当 H+、K+ 和 Pb2+ 离子载体发挥作用，已表现出有希望的抗癌活性。本研究的主要目的是研究其对结直肠癌细胞Wnt/β-catenin信号通路的抑制作用并阐明其潜在机制。我们将两种结肠直肠癌系（SW620 和 KM12）暴露于不同时间段内浓度不断增加的尼日利亚菌素，并评估了 50% 抑制浓度 (IC50) 值。我们的数据显示，尼日利亚菌素治疗以剂量和时间依赖性方式显着降低结直肠癌细胞中的肿瘤细胞增殖。随后的体外和体内实验表明，尼日利亚菌素可以显着抑制肿瘤的生长、迁移和侵袭，并诱导大肠癌细胞凋亡。我们的蛋白质印迹和免疫荧光测定结果表明，尼日利亚菌素可以抑制大肠癌细胞中的 Wnt/β-catenin 信号通路，并呈剂量依赖性地增加下游效应子和靶蛋白的表达。为了进一步阐明尼日利亚菌素通过 β-catenin 依赖性信号传导机制的抑制作用，我们建立了稳定的 β-catenin 过表达结直肠癌细胞。Western印迹、SuperTOPFlash荧光素酶报告基因和免疫沉淀试验均证实β-catenin是Wnt/β-catenin通路的关键中间体和参与者，尼日利亚菌素通过直接靶向β-catenin破坏复合物对结直肠癌细胞发挥抗癌作用。这些结果表明 Wnt/β-catenin 信号传导可能在结直肠癌进展中起重要作用。尼日利亚菌素靶向 Wnt/β-catenin 信号可能为尼日利亚菌素对癌细胞的分子机制提供新的见解，并提示可能在结直肠癌中的临床应用。摩尔癌症治疗; 17(5); 952-65。©2018 AACR。