title: The anthelmintic niclosamide inhibits colorectal cancer cell lines via modulation of the canonical and noncanonical Wnt signaling pathway.
abstract: Wnt/β-catenin signaling is known to play an important role in colorectal cancer (CRC). Niclosamide, a salicylamide derivative used in the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. The objective of this study was to investigate niclosamide as a therapeutic agent against CRC.
  
  
  
  The antiproliferative effects of 1, 3, 10, and 50 μM concentrations of niclosamide on human (SW480 and SW620) and rodent (CC531) CRC cell lines were determined by MTS assay and direct cell count. The lymphoid enhancer-binding factor 1/transcription factor (LEF/TCF) reporter assay monitored the activity of Wnt signaling. Immunofluorescence staining demonstrated the expression pattern of active β-catenin. Gene expression of canonical and noncanonical Wnt signaling components was analyzed using qRT-PCR. Western blot analysis was performed with antibodies detecting nuclear localization of β-catenin and c-jun.
  
  
  
  Cell proliferation in CRC cell lines was blocked dose dependently after 12 and 24 h of incubation. The Wnt promoter activity of LEF/TCF significantly decreased with niclosamide concentrations of 10 and 50 μM after 12 h of incubation. Active β-catenin did not shift from the nuclear to the cytosolic pool. However, canonical target genes (met, MMP7, and cyclin D1) as well as the coactivating factor Bcl9 were downregulated, whereas the noncanonical key player c-jun was clearly activated.
  
  
  
  Niclosamide treatment is associated with an inhibitory effect on CRC development and reduced Wnt activity. It may exert its effect by interfering with the nuclear β-catenin-Bcl9-LEF/TCF triple-complex and by upregulation of c-jun representing noncanonical Wnt/JNK signaling. Thus, our findings warrant further research into this substance as a treatment option for patients with advanced CRC.
authors.affiliation: Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany.
authors.forename: Malte B
authors.initials: MB
authors.lastname: Monin
authors.affiliation: Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Krause
authors.affiliation: Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Stelling
authors.affiliation: Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany.
authors.forename: Derya
authors.initials: D
authors.lastname: Bocuk
authors.affiliation: Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Niebert
authors.affiliation: Department of Haematology and Oncology, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Klemm
authors.affiliation: Department of Haematology and Oncology, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany; Department for Internal Medicine III, Hematology/Oncology, University Clinic Regensburg, Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
authors.affiliation: Department of General, Visceral and Paediatric Surgery, University Medical Centre, Georg-August-University Goettingen, Göttingen, Germany; University Hospital Wuerzburg, Julius-Maximilians-University Wuerzburg, Chair of Medical Teaching and Medical Education Research, Josef-Schneider-Str. 2/D6, D-97080 Wuerzburg, Germany. Electronic address: sarah.koenig@medizin.uni-goettingen.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Koenig
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D009534:Niclosamide / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D014408:Biomarkers, Tumor; D051176:beta Catenin; D009534:Niclosamide
keywords: CRC cell lines; Drug repositioning; Inhibition of canonical and noncanonical Wnt signaling; Niclosamide; Selective chemotherapeutic efficacy