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The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat

BACKGROUND/AIMS: Intestinal mucositis is a common side-effect in patients who receive aggressive chemotherapy. The Wnt signaling pathway is critical for establishing and maintaining the proliferative compartment of the intestine. In the present study, we tested whether Wnt/β-catenin signaling is inv...

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Autores principales: Sukhotnik, Igor, Geyer, Tatiana, Pollak, Yulia, Mogilner, Jorge G., Coran, Arnold G., Berkowitz, Drora
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222808/
https://www.ncbi.nlm.nih.gov/pubmed/25375224
http://dx.doi.org/10.1371/journal.pone.0110675
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author Sukhotnik, Igor
Geyer, Tatiana
Pollak, Yulia
Mogilner, Jorge G.
Coran, Arnold G.
Berkowitz, Drora
author_facet Sukhotnik, Igor
Geyer, Tatiana
Pollak, Yulia
Mogilner, Jorge G.
Coran, Arnold G.
Berkowitz, Drora
author_sort Sukhotnik, Igor
collection PubMed
description BACKGROUND/AIMS: Intestinal mucositis is a common side-effect in patients who receive aggressive chemotherapy. The Wnt signaling pathway is critical for establishing and maintaining the proliferative compartment of the intestine. In the present study, we tested whether Wnt/β-catenin signaling is involved in methotrexate (MTX)-induced intestinal damage in a rat model. METHODS: Non-pretreated and pretreated with MTX Caco-2 cells were evaluated for cell proliferation and apoptosis using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-2 animals were treated with a single dose of MTX given IP and were sacrificed on day 2, and MTX-4 rats were treated with MTX similar to group B and were sacrificed on day 4. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. Real Time PCR and Western blot was used to determine the level of Wnt/β-catenin related genes and protein expression. RESULTS: In the vitro experiment, treatment with MTX resulted in marked decrease in early cell proliferation rates following by a 17-fold increase in late cell proliferation rates compared to early proliferation. Treatment with MTX resulted in a significant increase in early and late apoptosis compared to Caco-2 untreated cells. In the vivo experiment, MTX-2 and MTX-4 rats demonstrated intestinal mucosal hypoplasia. MTX-2 rats demonstrated a significant decrease in FRZ-2, Wnt 3A Wnt 5A, β-catenin, c-myc mRNA expression and a significant decrease in β-catenin and Akt protein levels compared to control animals. Four days following MTX administration, rats demonstrated a trend toward a restoration of Wnt/β-catenin signaling especially in ileum. CONCLUSIONS: Wnt/β-catenin signaling is involved in enterocyte turnover during MTX-induced intestinal mucositis in a rat.
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spelling pubmed-42228082014-11-13 The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat Sukhotnik, Igor Geyer, Tatiana Pollak, Yulia Mogilner, Jorge G. Coran, Arnold G. Berkowitz, Drora PLoS One Research Article BACKGROUND/AIMS: Intestinal mucositis is a common side-effect in patients who receive aggressive chemotherapy. The Wnt signaling pathway is critical for establishing and maintaining the proliferative compartment of the intestine. In the present study, we tested whether Wnt/β-catenin signaling is involved in methotrexate (MTX)-induced intestinal damage in a rat model. METHODS: Non-pretreated and pretreated with MTX Caco-2 cells were evaluated for cell proliferation and apoptosis using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-2 animals were treated with a single dose of MTX given IP and were sacrificed on day 2, and MTX-4 rats were treated with MTX similar to group B and were sacrificed on day 4. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. Real Time PCR and Western blot was used to determine the level of Wnt/β-catenin related genes and protein expression. RESULTS: In the vitro experiment, treatment with MTX resulted in marked decrease in early cell proliferation rates following by a 17-fold increase in late cell proliferation rates compared to early proliferation. Treatment with MTX resulted in a significant increase in early and late apoptosis compared to Caco-2 untreated cells. In the vivo experiment, MTX-2 and MTX-4 rats demonstrated intestinal mucosal hypoplasia. MTX-2 rats demonstrated a significant decrease in FRZ-2, Wnt 3A Wnt 5A, β-catenin, c-myc mRNA expression and a significant decrease in β-catenin and Akt protein levels compared to control animals. Four days following MTX administration, rats demonstrated a trend toward a restoration of Wnt/β-catenin signaling especially in ileum. CONCLUSIONS: Wnt/β-catenin signaling is involved in enterocyte turnover during MTX-induced intestinal mucositis in a rat. Public Library of Science 2014-11-06 /pmc/articles/PMC4222808/ /pubmed/25375224 http://dx.doi.org/10.1371/journal.pone.0110675 Text en © 2014 Sukhotnik et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Sukhotnik, Igor
Geyer, Tatiana
Pollak, Yulia
Mogilner, Jorge G.
Coran, Arnold G.
Berkowitz, Drora
The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat
title The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat
title_full The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat
title_fullStr The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat
title_full_unstemmed The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat
title_short The Role of Wnt/β-Catenin Signaling in Enterocyte Turnover during Methotrexate-Induced Intestinal Mucositis in a Rat
title_sort role of wnt/β-catenin signaling in enterocyte turnover during methotrexate-induced intestinal mucositis in a rat
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222808/
https://www.ncbi.nlm.nih.gov/pubmed/25375224
http://dx.doi.org/10.1371/journal.pone.0110675
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