Glycyrrhetinic acid potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis

Introduction: Radix Glycyrrhiza has been used in China for thousand years to treat cancer. However, focus on its tumor-suppressing mechanism has been concentrated on its effect on tumor cell growth and apoptosis. Objectives: With the aid of a panel of human breast cancer cell lines, we reveal that glycyrrhetinic acid (GA), a major component of Radix Glycyrrhiza, is actually a significantly more potent agent to suppress invasion than cell survival. Results: GA effectively inhibits breast cancer cell MMP-2/MMP-9 expression; GA-induced reduction in the MMP-2/9 expression is apparently mediated by GA's ability to specifically inhibit the p38 MAPK activity and its downstream AP1 activation. Moreover, we show that GA down regulates the levels of Fra-1 and c-Jun, two main components of AP1 transcription complex in invasive breast cancer cells and that AP1-specific inhibitor abrogates breast cancer cell invasion. These results suggest that GA impairs the p38 MAPK-AP1 signaling axis, leading to the repression of breast cancer cell invasion. Finally, we demonstrate that GA effectively suppresses breast tumor outgrowth and pulmonary metastasis without causing animal weight loss or eliciting liver/kidney toxicity to the recipient animals. Conclusion: This study indicates that GA represents a good candidate compound for the potential development of therapeutic drug.