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Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention
In conventional research methods for cancer prevention, cell proliferation and apoptosis have been intensively targeted rather than the protection of normal or benign tumor cells from malignant transformation. In this study, we aimed to identify candidate colon cancer chemopreventive drugs based on...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470178/ https://www.ncbi.nlm.nih.gov/pubmed/30996256 http://dx.doi.org/10.1038/s41598-019-42363-y |
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author | Miyamoto, Shingo Narita, Takumi Komiya, Masami Fujii, Gen Hamoya, Takahiro Nakanishi, Ruri Tamura, Shuya Kurokawa, Yurie Takahashi, Maiko Mutoh, Michihiro |
author_facet | Miyamoto, Shingo Narita, Takumi Komiya, Masami Fujii, Gen Hamoya, Takahiro Nakanishi, Ruri Tamura, Shuya Kurokawa, Yurie Takahashi, Maiko Mutoh, Michihiro |
author_sort | Miyamoto, Shingo |
collection | PubMed |
description | In conventional research methods for cancer prevention, cell proliferation and apoptosis have been intensively targeted rather than the protection of normal or benign tumor cells from malignant transformation. In this study, we aimed to identify candidate colon cancer chemopreventive drugs based on the transcriptional activities of TCF/LEF, NF-κB and NRF2, that play important roles in the process of malignant transformation. We screened a “validated library” consisting of 1280 approved drugs to identify hit compounds that decreased TCF/LEF and NF-κB transcriptional activity and increased NRF2 transcriptional activity. Based on the evaluation of these 3 transcriptional activities, 8 compounds were identified as candidate chemopreventive drugs for colorectal cancer. One of those, itraconazole, is a clinically used anti-fungal drug and was examined in the Min mouse model of familial adenomatous polyposis. Treatment with itraconazole significantly suppressed intestinal polyp formation and the effects of itraconazole on transcriptional activities may be exerted partly through inhibition of intracellular cholesterol trafficking. This screen represents one of the first attempts to identify chemopreventive agents using integrated criteria consisting of the inhibition of TCF/LEF, NF-κB and induction of NRF2 transcriptional activity. |
format | Online Article Text |
id | pubmed-6470178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64701782019-04-23 Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention Miyamoto, Shingo Narita, Takumi Komiya, Masami Fujii, Gen Hamoya, Takahiro Nakanishi, Ruri Tamura, Shuya Kurokawa, Yurie Takahashi, Maiko Mutoh, Michihiro Sci Rep Article In conventional research methods for cancer prevention, cell proliferation and apoptosis have been intensively targeted rather than the protection of normal or benign tumor cells from malignant transformation. In this study, we aimed to identify candidate colon cancer chemopreventive drugs based on the transcriptional activities of TCF/LEF, NF-κB and NRF2, that play important roles in the process of malignant transformation. We screened a “validated library” consisting of 1280 approved drugs to identify hit compounds that decreased TCF/LEF and NF-κB transcriptional activity and increased NRF2 transcriptional activity. Based on the evaluation of these 3 transcriptional activities, 8 compounds were identified as candidate chemopreventive drugs for colorectal cancer. One of those, itraconazole, is a clinically used anti-fungal drug and was examined in the Min mouse model of familial adenomatous polyposis. Treatment with itraconazole significantly suppressed intestinal polyp formation and the effects of itraconazole on transcriptional activities may be exerted partly through inhibition of intracellular cholesterol trafficking. This screen represents one of the first attempts to identify chemopreventive agents using integrated criteria consisting of the inhibition of TCF/LEF, NF-κB and induction of NRF2 transcriptional activity. Nature Publishing Group UK 2019-04-17 /pmc/articles/PMC6470178/ /pubmed/30996256 http://dx.doi.org/10.1038/s41598-019-42363-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Miyamoto, Shingo Narita, Takumi Komiya, Masami Fujii, Gen Hamoya, Takahiro Nakanishi, Ruri Tamura, Shuya Kurokawa, Yurie Takahashi, Maiko Mutoh, Michihiro Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention |
title | Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention |
title_full | Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention |
title_fullStr | Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention |
title_full_unstemmed | Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention |
title_short | Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention |
title_sort | novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470178/ https://www.ncbi.nlm.nih.gov/pubmed/30996256 http://dx.doi.org/10.1038/s41598-019-42363-y |
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