Cargando…

IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression

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 investig...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Sang Chul, Kim, Ok-Hee, Lee, Sang Kuon, Kim, Say-June
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694979/
https://www.ncbi.nlm.nih.gov/pubmed/26450645
_version_ 1782407568018112512
author Lee, Sang Chul
Kim, Ok-Hee
Lee, Sang Kuon
Kim, Say-June
author_facet Lee, Sang Chul
Kim, Ok-Hee
Lee, Sang Kuon
Kim, Say-June
author_sort Lee, Sang Chul
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4694979
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-46949792016-01-20 IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression Lee, Sang Chul Kim, Ok-Hee Lee, Sang Kuon Kim, Say-June Oncotarget Research Paper 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. Impact Journals LLC 2015-09-16 /pmc/articles/PMC4694979/ /pubmed/26450645 Text en Copyright: © 2015 Lee et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Lee, Sang Chul
Kim, Ok-Hee
Lee, Sang Kuon
Kim, Say-June
IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression
title IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression
title_full IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression
title_fullStr IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression
title_full_unstemmed IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression
title_short IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression
title_sort iwr-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing wnt/β-catenin signaling as well as survivin expression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694979/
https://www.ncbi.nlm.nih.gov/pubmed/26450645
work_keys_str_mv AT leesangchul iwr1inhibitsepithelialmesenchymaltransitionofcolorectalcancercellsthroughsuppressingwntbcateninsignalingaswellassurvivinexpression
AT kimokhee iwr1inhibitsepithelialmesenchymaltransitionofcolorectalcancercellsthroughsuppressingwntbcateninsignalingaswellassurvivinexpression
AT leesangkuon iwr1inhibitsepithelialmesenchymaltransitionofcolorectalcancercellsthroughsuppressingwntbcateninsignalingaswellassurvivinexpression
AT kimsayjune iwr1inhibitsepithelialmesenchymaltransitionofcolorectalcancercellsthroughsuppressingwntbcateninsignalingaswellassurvivinexpression