title: IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression.
abstract: Aberrant activation of Wnt/β-catenin signaling is frequently observed in patients with colorectal cancer (CRC) and is considered a major determinant of CRC pathogenesis. CRC pathogenesis is particularly accompanied by epithelial-mesenchymal transition (EMT) and survivin expression. Here, we investigated the potential and mechanism of a novel Wnt/β-catenin inhibitor IWR-1 to suppress tumor metastasis in relation with EMT and survivin expression. We first determined the EMT reversal effects of IWR-1 in in vitro (HCT116 and HT29 cells) and ex vivo (specimens of CRC patients) CRC models. It was shown that IWR-1 inhibited cell proliferation and EMT even in the presence of TNF-α-induced cancer cell stimulation. IWR-1 also significantly suppressed cell migration, invasion, and matrix metalloproteinase activities of CRC cell lines. Furthermore, we showed the evidence that IWR-1 provides EMT reversal effects by directly suppressing survivin expression by the followings: 1) IWR-1 could not completely inhibit EMT in survivin-overexpressing HCT116 cells, 2) EMT reversal effects of IWR-1 were more pronounced in survivin-suppressed cells, and 3) Survivin promoter assay directly identified the survivin promoter region responsible for inhibition of survivin transcription by IWR-1. Taken altogether, our results demonstrate that IWR-1 has the potential to suppress tumor metastasis by inhibiting Wnt/β-catenin pathway as well as survivin expression. Therefore, IWR-1 could be considered for future clinical use as a therapeutic agent to treat CRC.
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea.
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Kim
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea.
authors.forename: Sang Kuon
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea.
authors.forename: Say-June
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007094:Imides / Q000494:pharmacology*; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D000077022:Survivin; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; C495270:CTNNB1 protein, human; C585534:IWR-1 compound; D007094:Imides; D051034:Inhibitor of Apoptosis Proteins; D011804:Quinolines; D000077022:Survivin; D051153:Wnt Proteins; D051176:beta Catenin; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: IWR-1; colorectal cancer; epithelial mesenchymal transition (EMT); survivin; wnt/β-catenin signaling