Cargando…

5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation

Cell migration is an essential step for tumor metastasis. The small GTPase Rac1 plays an important role in cell migration. Previously, we reported that epidermal growth factor (EGF) induced two waves of Rac1 activation; namely, at 5 min and 12 h after stimulation. A second wave of EGF-induced Rac1 a...

Descripción completa

Detalles Bibliográficos
Autores principales: Magi, Shigeyuki, Takemoto, Yasushi, Kobayashi, Hiroki, Kasamatsu, Masato, Akita, Takahiro, Tanaka, Ayako, Takano, Kei, Tashiro, Etsu, Igarashi, Yasuhiro, Imoto, Masaya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317946/
https://www.ncbi.nlm.nih.gov/pubmed/24350867
http://dx.doi.org/10.1111/cas.12340
_version_ 1782355764783874048
author Magi, Shigeyuki
Takemoto, Yasushi
Kobayashi, Hiroki
Kasamatsu, Masato
Akita, Takahiro
Tanaka, Ayako
Takano, Kei
Tashiro, Etsu
Igarashi, Yasuhiro
Imoto, Masaya
author_facet Magi, Shigeyuki
Takemoto, Yasushi
Kobayashi, Hiroki
Kasamatsu, Masato
Akita, Takahiro
Tanaka, Ayako
Takano, Kei
Tashiro, Etsu
Igarashi, Yasuhiro
Imoto, Masaya
author_sort Magi, Shigeyuki
collection PubMed
description Cell migration is an essential step for tumor metastasis. The small GTPase Rac1 plays an important role in cell migration. Previously, we reported that epidermal growth factor (EGF) induced two waves of Rac1 activation; namely, at 5 min and 12 h after stimulation. A second wave of EGF-induced Rac1 activation was required for EGF-induced cell migration, however, the spatiotemporal regulation of the second wave of EGF-induced Rac1 activation remains largely unclear. In this study, we found that 5-lipoxygenase (5-LOX) is activated in the process of EGF-induced cell migration, and that leukotriene C(4) (LTC(4)) produced by 5-LOX mediated the second wave of Rac1 activation, as well as cell migration. Furthermore, these effects caused by LTC(4) were found to be blocked in the presence of the antagonist of cysteinyl leukotriene receptor 1 (CysLT1). This blockage indicates that LTC(4)-mediated CysLT1 signaling regulates the second EGF-induced wave of Rac1 activation. We also found that 5-LOX inhibitors, CysLT1 antagonists and the knockdown of CysLT1 inhibited EGF-induced T cell lymphoma invasion and metastasis-inducing protein 1 (Tiam1) expression. Tiam1 expression is required for the second wave of EGF-induced Rac1 activation in A431 cells. Therefore, our results indicate that the 5-LOX/LTC(4)/CysLT1 signaling pathway regulates EGF-induced cell migration by increasing Tiam1 expression, leading to a second wave of Rac1 activation. Thus, CysLT1 may serve as a new molecular target for antimetastatic therapy. In addition, the CysLT1 antagonist, montelukast, which is used clinically for allergy treatment, might have great potential as a novel type of antimetastatic agent.
format Online
Article
Text
id pubmed-4317946
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BlackWell Publishing Ltd
record_format MEDLINE/PubMed
spelling pubmed-43179462015-10-05 5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation Magi, Shigeyuki Takemoto, Yasushi Kobayashi, Hiroki Kasamatsu, Masato Akita, Takahiro Tanaka, Ayako Takano, Kei Tashiro, Etsu Igarashi, Yasuhiro Imoto, Masaya Cancer Sci Original Articles Cell migration is an essential step for tumor metastasis. The small GTPase Rac1 plays an important role in cell migration. Previously, we reported that epidermal growth factor (EGF) induced two waves of Rac1 activation; namely, at 5 min and 12 h after stimulation. A second wave of EGF-induced Rac1 activation was required for EGF-induced cell migration, however, the spatiotemporal regulation of the second wave of EGF-induced Rac1 activation remains largely unclear. In this study, we found that 5-lipoxygenase (5-LOX) is activated in the process of EGF-induced cell migration, and that leukotriene C(4) (LTC(4)) produced by 5-LOX mediated the second wave of Rac1 activation, as well as cell migration. Furthermore, these effects caused by LTC(4) were found to be blocked in the presence of the antagonist of cysteinyl leukotriene receptor 1 (CysLT1). This blockage indicates that LTC(4)-mediated CysLT1 signaling regulates the second EGF-induced wave of Rac1 activation. We also found that 5-LOX inhibitors, CysLT1 antagonists and the knockdown of CysLT1 inhibited EGF-induced T cell lymphoma invasion and metastasis-inducing protein 1 (Tiam1) expression. Tiam1 expression is required for the second wave of EGF-induced Rac1 activation in A431 cells. Therefore, our results indicate that the 5-LOX/LTC(4)/CysLT1 signaling pathway regulates EGF-induced cell migration by increasing Tiam1 expression, leading to a second wave of Rac1 activation. Thus, CysLT1 may serve as a new molecular target for antimetastatic therapy. In addition, the CysLT1 antagonist, montelukast, which is used clinically for allergy treatment, might have great potential as a novel type of antimetastatic agent. BlackWell Publishing Ltd 2014-03 2014-01-28 /pmc/articles/PMC4317946/ /pubmed/24350867 http://dx.doi.org/10.1111/cas.12340 Text en © 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Magi, Shigeyuki
Takemoto, Yasushi
Kobayashi, Hiroki
Kasamatsu, Masato
Akita, Takahiro
Tanaka, Ayako
Takano, Kei
Tashiro, Etsu
Igarashi, Yasuhiro
Imoto, Masaya
5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation
title 5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation
title_full 5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation
title_fullStr 5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation
title_full_unstemmed 5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation
title_short 5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation
title_sort 5-lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through tiam1 upregulation and rac1 activation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317946/
https://www.ncbi.nlm.nih.gov/pubmed/24350867
http://dx.doi.org/10.1111/cas.12340
work_keys_str_mv AT magishigeyuki 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT takemotoyasushi 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT kobayashihiroki 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT kasamatsumasato 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT akitatakahiro 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT tanakaayako 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT takanokei 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT tashiroetsu 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT igarashiyasuhiro 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation
AT imotomasaya 5lipoxygenaseandcysteinylleukotrienereceptor1regulateepidermalgrowthfactorinducedcellmigrationthroughtiam1upregulationandrac1activation