期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 176, 期 17, 页码 3390-3406出版社
WILEY
DOI: 10.1111/bph.14770
关键词
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资金
- Shenzhen Basic Research Program [JCYJ20150525092941006, JCYJ20150525092941030, JCYJ20170302143447936]
- Key Laboratory Project of Shenzhen [ZDSY20130329101130496]
- Science and Technology Program of Guangdong Province in China [2017B030301016]
- Shenzhen Peacock Innovation Team Project [KQTD20140630100658078]
- Nature Science Foundation of Guangdong Province [2014A030310168]
- National Nature Science Foundation of China [31501143, 31870754, 81372342]
Background and Purpose Salinomycin is a well-known inhibitor of human cancer stem cells (CSCs). However, the molecular mechanism(s) by which salinomycin targets colorectal CSCs is poorly understood. Here, we have investigated underlying antitumour mechanisms of salinomycin in colorectal cancer cells and three tumour models. Experimental Approach The inhibitory effect of salinomycin on the Wnt/beta-catenin pathway was analysed with the SuperTopFlash reporter system. The mRNA expression of Wnt target genes was evaluated with real-time PCR. Effects of salinomycin on beta-catenin/TCF4E interaction were examined using co-immunoprecipitation and an in vitro GST pull-down assay. Cell proliferation was determined by BrdU incorporation and soft agar colony formation assay. The stemness of the cells was assessed by sphere formation assay. Antitumour effects of salinomycin on colorectal cancers was evaluated with colorectal CSC xenografts, APC(min/+) transgenic mice, and patient-derived colorectal tumour xenografts. Key Results Salinomycin blocked beta-catenin/TCF4E complex formation in colorectal cancer cells and in an in vitro GST pull-down assay, thus decreasing expression of Wnt target genes. Salinomycin also suppressed the transcriptional activity mediated by beta-catenin/LEF1 or beta-catenin/TCF4E complex and exhibited an inhibitory effect on the sphere formation, proliferation, and anchorage-independent growth of colorectal cancer cells. In colorectal tumour xenografts and APC(min/+) transgenic mice, administration of salinomycin significantly reduced tumour growth and the expression of CSC-related Wnt target genes including LGR5. Conclusions and Implications Our study suggested that salinomycin could suppress the growth of colorectal cancer by disrupting the beta-catenin/TCF complex and thus may be a promising agent for colorectal cancer treatment.
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