Open Access5‐Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor‐induced cell migration through T iam1 upregulation and R ac1 activation
Author(s) -
Magi Shigeyuki,
Takemoto Yasushi,
Kobayashi Hiroki,
Kasamatsu Masato,
Akita Takahiro,
Tanaka Ayako,
Takano Kei,
Tashiro Etsu,
Igarashi Yasuhiro,
Imoto Masaya
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12340
Subject(s) - rac1 , cell migration , epidermal growth factor , microbiology and biotechnology , downregulation and upregulation , cancer research , signal transduction , chemistry , biology , cell , receptor , biochemistry , gene
Cell migration is an essential step for tumor metastasis. The small GTP ase R ac1 plays an important role in cell migration. Previously, we reported that epidermal growth factor ( EGF ) induced two waves of R ac1 activation; namely, at 5 min and 12 h after stimulation. A second wave of EGF ‐induced R ac1 activation was required for EGF ‐induced cell migration, however, the spatiotemporal regulation of the second wave of EGF ‐induced R ac1 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 R ac1 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 ( C ys LT 1). This blockage indicates that LTC 4 ‐mediated C ys LT 1 signaling regulates the second EGF ‐induced wave of R ac1 activation. We also found that 5‐ LOX inhibitors, C ys LT 1 antagonists and the knockdown of C ys LT 1 inhibited EGF ‐induced T cell lymphoma invasion and metastasis‐inducing protein 1 ( T iam1) expression. T iam1 expression is required for the second wave of EGF ‐induced R ac1 activation in A 431 cells. Therefore, our results indicate that the 5‐ LOX / LTC 4 /Cys LT 1 signaling pathway regulates EGF ‐induced cell migration by increasing T iam1 expression, leading to a second wave of R ac1 activation. Thus, C ys LT 1 may serve as a new molecular target for antimetastatic therapy. In addition, the C ys LT 1 antagonist, montelukast, which is used clinically for allergy treatment, might have great potential as a novel type of antimetastatic agent.