5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation.
Bottom Line: In this study, we found that 5-lipoxygenase (5-LOX) is activated in the process of EGF-induced cell migration, and that leukotriene C4 (LTC4 ) produced by 5-LOX mediated the second wave of Rac1 activation, as well as cell migration.Furthermore, these effects caused by LTC4 were found to be blocked in the presence of the antagonist of cysteinyl leukotriene receptor 1 (CysLT1).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.
Affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.Show MeSH
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Mentions: We suggest a model for the mechanism regulating the second EGF-induced wave of Rac1 activation in the process of cell migration, as shown in Figure6. Our findings indicate that crosstalk between EGFR signaling and CysLT1 signaling is essential for epithelial cancer migration and invasion. This hypothesis is consistent with our previous chemical genomic study, which predicted that CysLT1 signaling might be closely related to Taim1-mediated Rac1 activation.38 Thus, CysLT1 is a core element of the regulating mechanism of cell migration and the second wave of Rac1 activation in our model. This may serve as a new molecular target for antimetastatic therapy. Because montelukast is already put on the market as a clinical drug for allergies, it also has great potential as an antimetastatic agent against a subset of cancer cells.
Affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.