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

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 constitutiv...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5940ff3a36064ed8b71265154b006e7d
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spelling	oai:doaj.org-article:5940ff3a36064ed8b71265154b006e7d2021-12-02T15:08:12ZTranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells10.1038/s41598-018-24484-y2045-2322https://doaj.org/article/5940ff3a36064ed8b71265154b006e7d2018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-24484-yhttps://doaj.org/toc/2045-2322Abstract 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.Ritsuko HarigaiShigeki SakaiHiroyuki NobusueChikako HiroseOltea SampetreanNoriaki MinamiYukie HataTakashi KasamaTakanori HiroseToshiki TakenouchiKenjiro KosakiKazuo KishiHideyuki SayaYoshimi ArimaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells
description	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.
format	article
author	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
author_facet	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
author_sort	Ritsuko Harigai
title	Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells
title_short	Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells
title_full	Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells
title_fullStr	Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells
title_full_unstemmed	Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells
title_sort	tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/5940ff3a36064ed8b71265154b006e7d
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Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells

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