Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells

Ritsuko Harigai, Shigeki Sakai, Hiroyuki Nobusue, Chikako Hirose, Oltea Sampetrean, Noriaki Minami, Yukie Hata, Takashi Kasama, Takanori Hirose, Toshiki Takenouchi, Kenjiro Kosaki, Kazuo Kishi, Hideyuki Saya, Yoshimi Arima

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Abstract

Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas. With the use of a cell-based drug screening assay, we have now identified the antiallergy drug tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) as an inhibitor of EMT and found that it attenuated the expression of mesenchymal markers and angiogenesis-related genes in NF1-mutated sNF96.2 cells and in neurofibroma cells from NF1 patients. Tranilast also suppressed the proliferation of neurofibromin-deficient cells in vitro more effectively than it did that of intact cells. In addition, tranilast inhibited sNF96.2 cell migration and proliferation in vivo. Knockdown of type III collagen (COL3A1) also suppressed the proliferation of neurofibroma cells, whereas expression of COL3A1 and SOX2 was increased in tranilast-resistant cells, suggesting that COL3A1 and the transcription factor SOX2 might contribute to the development of tranilast resistance.

Original languageEnglish
Article number6069
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Neurofibromin 1
Neurofibromatosis 1
Epithelial-Mesenchymal Transition
Neurofibroma
Gene Expression
SOXB1 Transcription Factors
Neurofibromatosis 1 Genes
Cell Proliferation
Tumor Suppressor Proteins
Preclinical Drug Evaluations
Collagen Type III
Monomeric GTP-Binding Proteins
Germ-Line Mutation
tranilast
Cell Movement
Mutation

ASJC Scopus subject areas

  • General

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Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells. / Harigai, Ritsuko; Sakai, Shigeki; Nobusue, Hiroyuki; Hirose, Chikako; Sampetrean, Oltea; Minami, Noriaki; Hata, Yukie; Kasama, Takashi; Hirose, Takanori; Takenouchi, Toshiki; Kosaki, Kenjiro; Kishi, Kazuo; Saya, Hideyuki; Arima, Yoshimi.

In: Scientific Reports, Vol. 8, No. 1, 6069, 01.12.2018.

Research output: Contribution to journalArticle

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AU - Sampetrean, Oltea

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