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

Abstract 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.