Open AccessIdentification of a small‐molecule ligand of β ‐arrestin1 as an inhibitor of stromal fibroblast cell migration accelerated by cancer cells
Author(s) -
Suvarna Kruthi,
Honda Kaori,
Kondoh Yasumitsu,
Osada Hiroyuki,
Watanabe Nobumoto
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1339
Subject(s) - fibroblast activation protein, alpha , stromal cell , fibroblast , cancer cell , cancer research , cancer associated fibroblasts , chemistry , microbiology and biotechnology , metastasis , wound healing , cancer , biology , in vitro , biochemistry , immunology , genetics
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).