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Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

Klose, Johannes ; Eissele, Jana ; Volz, Claudia ; Schmitt, Steffen ; Ritter, Alina ; Ying, Shen ; Schmidt, Thomas ; Heger, Ulrike ; Schneider, Martin ; Ulrich, Alexis

In: BMC Cancer, 16 (2016), Nr. 896. pp. 1-15. ISSN 1471-2407

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Download (2MB) | Lizenz: Creative Commons LizenzvertragSalinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells by Klose, Johannes ; Eissele, Jana ; Volz, Claudia ; Schmitt, Steffen ; Ritter, Alina ; Ying, Shen ; Schmidt, Thomas ; Heger, Ulrike ; Schneider, Martin ; Ulrich, Alexis underlies the terms of Creative Commons Attribution 3.0 Germany

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Abstract

Background: The polyether antibiotic Salinomycin (Sal) is regarded as an inhibitor of cancer stem cells. Its effectiveness on human colorectal cancer (CRC) cells in vitro has been demonstrated before. The aim of this study was to establish a murine model to investigate the effectiveness of Sal in vivo. Furthermore, we investigated the impact of Sal on Wnt/β-catenin signaling in human CD133+ CRC cells. Methods: The two murine CRC cell lines MC38 and CT26 were used to analyze the impact of Sal on tumor cell proliferation, viability, migration, cell cycle progression and cell death in vitro. For in vivo studies, CT26 cells were injected into syngeneic BALB/c mice to initiate (i) subcutaneous, (ii) orthotopic, or (iii) metastatic CRC growth. Sal was administered daily, 5-Fluoruracil served as a control. For mechanistic studies, the CD133+and CD133- subpopulations of human CRC cells were separated by flow cytometry and separately exposed to increasing concentrations of Sal. The impact on Wnt/β-catenin signaling was determined by Western blotting and quantitative PCR. Results: Sal markedly impaired tumor cell viability, proliferation and migration, and induced necrotic cell death in vitro. CRC growth in vivo was likewise inhibited upon Sal treatment. Interference with Wnt signaling and reduced expression of the Wnt target genes Fibronectin and Lgr5 indicates a novel molecular mechanism, mediating anti-tumoral effects of Sal in CRC. Conclusion: Sal effectively impairs CRC growth in vivo. Furthermore, Sal acts as an inhibitor of Wnt/β-catenin signaling. Thus, Salinomycin represents a promising candidate for clinical CRC treatment.

Item Type: Article
Journal or Publication Title: BMC Cancer
Volume: 16
Number: 896
Publisher: BioMed Central; Springer
Place of Publication: London; Berlin; Heidelberg
Date Deposited: 22 Nov 2016 13:30
Date: 2016
ISSN: 1471-2407
Page Range: pp. 1-15
Faculties / Institutes: Service facilities > German Cancer Research Center (DKFZ)
Medizinische Fakultät Heidelberg > Chirurgische Universitätsklinik
Subjects: 610 Medical sciences Medicine
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