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.