Suppression of EGF-induced tumor cell migration and matrix metalloproteinase-9 expression by capsaicin via the inhibition of EGFR-mediated FAK/Akt, PKC/Raf/ERK, p38 MAPK, and AP-1 signaling

Scope: Capsaicin is a cancer-suppressing agent. The aim of our study was to determine the effect of capsaicin on tumor invasion and migration; the possible mechanisms involved in this inhibition were investigated in human fibrosarcoma cells. Methods and results: We employed invasion, migration and gelatin zymography assays to characterize the effect of capsaicin on HT-1080 cells. Transient transfection assays and immunoblot analysis were performed to study its molecular mechanisms of action. Capsaicin inhibited the epidermal growth factor (EGF)-induced activation of matrix metalloproteinase (MMP)-9 and MMP-2, and further inhibited cell invasion and migration. Capsaicin decreased the EGF-induced expression of MMP-9, MMP-2, and MT1-MMP, but did not alter TIMP-1 and TIMP-2 levels. Capsaicin suppressed EGF-induced c-Jun and c-Fos nuclear translocation, and also abrogated the EGF-induced phosphorylation of EGF receptor (EGFR), focal adhesion kinase (FAK), protein kinase C (PKC), phosphatidylinositol 3-Kinase (PI3K)/Akt, extracellular regulated kinase (ERK)1/2, and JNK1/2, an upstream modulator of AP-1. Furthermore, the EGFR inhibitor inhibited EGF-induced MMP-9 expression, as well as AP-1 activity and cell migration. Conclusion: Capsaicin inhibited the EGF-induced invasion and migration of human fibrosarcoma cells via EGFR-dependent FAK/Akt, PKC/Raf/ERK, p38 mitogen-activated protein kinase (MAPK), and AP-1 signaling, leading to the down-regulation of MMP-9 expression. These results indicate the role of capsaicin as a potent anti-metastatic agent, which can markedly inhibit the metastatic and invasive capacity of fibrosarcoma cells.