In:
Cancer Medicine, Wiley, Vol. 7, No. 3 ( 2018-03), p. 883-893
Abstract:
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; CAF s) might aid in the improved treatment of cancer metastasis. NIH 3T3 fibroblasts cocultured with MCF 7 cells displayed enhanced migration compared to NIH 3T3 fibroblasts cultured alone. We used this system to identify the small‐molecule inhibitors responsible for their enhanced migration, a characteristic of CAF s. 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. RKN 5755 was identified as a selective inhibitor of activated fibroblasts. RKN 5755 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).
Type of Medium:
Online Resource
ISSN:
2045-7634
,
2045-7634
DOI:
10.1002/cam4.2018.7.issue-3
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2659751-2
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