Frondoside A has an anti-invasive effect by inhibiting TPA-induced MMP-9 activation via NF-κB and AP-1 signaling in human breast cancer cells

Abstract

Metastasis and invasion are among the main causes of death in patients with malignant tumors. The aim of this study was to determine the anti-invasive activity of frondoside A against human breast cancer cells. We investigated the inhibitory effect of frondoside A on cell clonogenicity, invasion and migration in TPA-stimulated human breast cancer cells at non-cytotoxic concentrations. Frondoside A significantly attenuated TPA-induced colony formation, invasion and migration in MBA-MB-231 human breast cancer cells. Induction of MMP-9 is especially important for the metastasis of many cancer tumor cell types. Additionally, we found that frondoside A suppresses TPA-induced MMP-9 enzymatic activity, secretion and expression. This effect was associated with reduced activation of AP-1 and NF-κB, and correlated with enhanced expression of TIMP-1 and TIMP-2. Frondoside A significantly inhibited the TPA-induced MMP-9 expression possibly via the suppression of AP-1 and NF-κB signaling pathways. Frondoside A reduces the activation of the PI3K/Akt, ERK1/2 and p38 MAPK signals. These results suggest that the anti-metastatic effects of frondoside A on human breast cancer cells might result from inhibited TPA activation of AP-1 and NF-κB and reduced TPA activation of PI3K/Akt, ERK1/2 and p38 MAPK signals, ultimately leading to downregulation of MMP-9 expression. These results indicate the role of frondoside A in metastasis and its underlying molecular mechanisms, thus, suggesting frondoside A as a chemopreventive agent for metastatic breast cancer.