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Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells

Stromal fibroblasts, which occupy a major portion of the tumor microenvironment, play an important role in cancer metastasis. Thus, targeting of these fibroblasts activated by cancer cells (carcinoma‐associated fibroblasts; CAFs) might aid in the improved treatment of cancer metastasis. NIH3T3 fibro...

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Autores principales: Suvarna, Kruthi, Honda, Kaori, Kondoh, Yasumitsu, Osada, Hiroyuki, Watanabe, Nobumoto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852355/
https://www.ncbi.nlm.nih.gov/pubmed/29380537
http://dx.doi.org/10.1002/cam4.1339
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author Suvarna, Kruthi
Honda, Kaori
Kondoh, Yasumitsu
Osada, Hiroyuki
Watanabe, Nobumoto
author_facet Suvarna, Kruthi
Honda, Kaori
Kondoh, Yasumitsu
Osada, Hiroyuki
Watanabe, Nobumoto
author_sort Suvarna, Kruthi
collection PubMed
description Stromal fibroblasts, which occupy a major portion of the tumor microenvironment, play an important role in cancer metastasis. Thus, targeting of these fibroblasts activated by cancer cells (carcinoma‐associated fibroblasts; CAFs) might aid in the improved treatment of cancer metastasis. NIH3T3 fibroblasts cocultured with MCF7 cells displayed enhanced migration compared to NIH3T3 fibroblasts cultured alone. We used this system to identify the small‐molecule inhibitors responsible for their enhanced migration, a characteristic of CAFs. We selected β‐arrestin1, which showed high expression in cocultured cells, as a molecular target for such inhibitors. Cofilin, a protein downstream of β‐arrestin1, is activated/dephosphorylated in this condition. The small‐molecule ligands of β‐arrestin1 obtained by chemical array were then examined using a wound healing coculture assay. RKN5755 was identified as a selective inhibitor of activated fibroblasts. RKN5755 inhibited the enhanced migration of fibroblasts cocultured with cancer cells by binding to β‐arrestin1 and interfering with β‐arrestin1‐mediated cofilin signaling pathways. Therefore, these results demonstrate the role of β‐arrestin1 in the activation of fibroblasts and inhibiting this protein by small molecule inhibitor might be a potential therapeutic target for the stromal fibroblast activation (cancer–stroma interaction).
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spelling pubmed-58523552018-03-22 Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells Suvarna, Kruthi Honda, Kaori Kondoh, Yasumitsu Osada, Hiroyuki Watanabe, Nobumoto Cancer Med Cancer Biology Stromal fibroblasts, which occupy a major portion of the tumor microenvironment, play an important role in cancer metastasis. Thus, targeting of these fibroblasts activated by cancer cells (carcinoma‐associated fibroblasts; CAFs) might aid in the improved treatment of cancer metastasis. NIH3T3 fibroblasts cocultured with MCF7 cells displayed enhanced migration compared to NIH3T3 fibroblasts cultured alone. We used this system to identify the small‐molecule inhibitors responsible for their enhanced migration, a characteristic of CAFs. We selected β‐arrestin1, which showed high expression in cocultured cells, as a molecular target for such inhibitors. Cofilin, a protein downstream of β‐arrestin1, is activated/dephosphorylated in this condition. The small‐molecule ligands of β‐arrestin1 obtained by chemical array were then examined using a wound healing coculture assay. RKN5755 was identified as a selective inhibitor of activated fibroblasts. RKN5755 inhibited the enhanced migration of fibroblasts cocultured with cancer cells by binding to β‐arrestin1 and interfering with β‐arrestin1‐mediated cofilin signaling pathways. Therefore, these results demonstrate the role of β‐arrestin1 in the activation of fibroblasts and inhibiting this protein by small molecule inhibitor might be a potential therapeutic target for the stromal fibroblast activation (cancer–stroma interaction). John Wiley and Sons Inc. 2018-01-29 /pmc/articles/PMC5852355/ /pubmed/29380537 http://dx.doi.org/10.1002/cam4.1339 Text en © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cancer Biology
Suvarna, Kruthi
Honda, Kaori
Kondoh, Yasumitsu
Osada, Hiroyuki
Watanabe, Nobumoto
Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
title Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
title_full Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
title_fullStr Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
title_full_unstemmed Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
title_short Identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
title_sort identification of a small‐molecule ligand of β‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852355/
https://www.ncbi.nlm.nih.gov/pubmed/29380537
http://dx.doi.org/10.1002/cam4.1339
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