Angiotensin II (Ang II), a biologically active peptide of the renin-angiotensin system (RAS), plays an important role in promoting cell migration via Angiotensin II type 1 receptor (AT1R). In this study, we examined the mechanisms by which Ang II affected cell migration in AT1R-positive MDA-MB-231 human breast cancer cells. Ang II increased cell migration and expression of matrix metalloproteinase (MMP)-2,-9 in a dose-dependent manner. Ang II-mediated cell migration was reduced by specific blocking of MMP-2 and MMP-9, as well as with pretreatment with inhibitors of AT1R, phosphatidylinositol 3-kinase (PI3K), Akt, and NF-κB. Similarly, Ang II-mediated expression of MMP-2,-9 was downregulated by pretreatment with inhibitors of AT1R and PI3K. In addition, Ang II treatment significantly induced phosphorylation of PI3K, Akt, and resulted in increased NF-κB activity. These findings suggest that Ang II activates the AT1R/PI3K/Akt pathway, which further activates IKKα/β and NF-κB, resulting in enhanced expression of MMP-2,-9 and migration in human breast cancer cells. Therefore, targeting Ang II/AT1R/PI3K/Akt/NF-κB signaling could be a novel anti-metastatic therapy for breast cancer.
© 2014 Wiley Periodicals, Inc.