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Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex
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 cell...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692576/ https://www.ncbi.nlm.nih.gov/pubmed/31236922 http://dx.doi.org/10.1111/bph.14770 |
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author | Wang, Zhongyuan Zhou, Liang Xiong, Yanpeng Yu, Shubin Li, Huan Fan, Jiaoyang Li, Fan Su, Zijie Song, Jiaxing Sun, Qi Liu, Shan‐Shan Xia, Yuqing Zhao, Liang Li, Shiyue Guo, Fang Huang, Peng Carson, Dennis A. Lu, Desheng |
author_facet | Wang, Zhongyuan Zhou, Liang Xiong, Yanpeng Yu, Shubin Li, Huan Fan, Jiaoyang Li, Fan Su, Zijie Song, Jiaxing Sun, Qi Liu, Shan‐Shan Xia, Yuqing Zhao, Liang Li, Shiyue Guo, Fang Huang, Peng Carson, Dennis A. Lu, Desheng |
author_sort | Wang, Zhongyuan |
collection | PubMed |
description | 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/β‐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 β‐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 β‐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 β‐catenin/LEF1 or β‐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 β‐catenin/TCF complex and thus may be a promising agent for colorectal cancer treatment. |
format | Online Article Text |
id | pubmed-6692576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66925762019-08-19 Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex Wang, Zhongyuan Zhou, Liang Xiong, Yanpeng Yu, Shubin Li, Huan Fan, Jiaoyang Li, Fan Su, Zijie Song, Jiaxing Sun, Qi Liu, Shan‐Shan Xia, Yuqing Zhao, Liang Li, Shiyue Guo, Fang Huang, Peng Carson, Dennis A. Lu, Desheng Br J Pharmacol Research Papers 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/β‐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 β‐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 β‐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 β‐catenin/LEF1 or β‐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 β‐catenin/TCF complex and thus may be a promising agent for colorectal cancer treatment. John Wiley and Sons Inc. 2019-07-24 2019-09 /pmc/articles/PMC6692576/ /pubmed/31236922 http://dx.doi.org/10.1111/bph.14770 Text en © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Papers Wang, Zhongyuan Zhou, Liang Xiong, Yanpeng Yu, Shubin Li, Huan Fan, Jiaoyang Li, Fan Su, Zijie Song, Jiaxing Sun, Qi Liu, Shan‐Shan Xia, Yuqing Zhao, Liang Li, Shiyue Guo, Fang Huang, Peng Carson, Dennis A. Lu, Desheng Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex |
title | Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex |
title_full | Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex |
title_fullStr | Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex |
title_full_unstemmed | Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex |
title_short | Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex |
title_sort | salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/t‐cell factor complex |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692576/ https://www.ncbi.nlm.nih.gov/pubmed/31236922 http://dx.doi.org/10.1111/bph.14770 |
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