title: Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+human colorectal cancer cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. Johannes.Klose@med.uni-heidelberg.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Klose
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Eissele
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Volz
authors.affiliation: German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Ritter
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Shen
authors.initials: S
authors.lastname: Ying
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heger
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Ulrich
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D011714:Pyrans / Q000008:administration & dosage* / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D000071916:AC133 Antigen; D011714:Pyrans; C000606023:PROM1 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: Animal model; Colorectal cancer; Salinomycin; Wnt/β-catenin pathway