Differential regulation of activator protein 1 activity by glycyrrhizin

Glycyrrhizin, a major component of Glycyrrhiza uralensis (licorice) root, is a saponin and exhibits a number of pharmacological effects, including anti-inflammation, anti-ulcer, anti-allergy, and anticarcinogenesis. Activator protein I (AP-1), a nuclear transcription factor, consists of Jun/Fos heterodimers or Jun/Jun homodimers, and blocking of tumor promoter-induced AP-1 activity could inhibit induced cellular transformation. In order to elucidate the molecular mechanism of glycyrrhizin-induced anticarcinogenesis, effect of glycyrrhizin on the AP-1 activity in untreated and tumor promoter-12-O-tetradecanoylphorbol-13-acetate (TPA)-treated conditions was analyzed in this study. Glycyrrhizin induced the AP-1/TATA reporter activity in a dose-dependent fashion, which was judged by chloramphenicol acetyltransferase assay and electrophoretic mobility-shift assay. Similar results were observed in HepG2 and Vero cells, suggested that glycyrrhizin effect was cell type-independent. In addition, the cis element responsible for glycyrrhizin activity was AP-1 responsive element. Further analysis indicated that glycyrrhizin exhibited a different regulation on the AP-1 activity in untreated and TPA-treated cells. Glycyrrhizin induced the AP-1 activity in untreated cells, while it inhibited the TPA-induced AP-1 activation in TPA-treated cells. These results provide insight into the biological actions of glycyrrhizin and the molecular basis for the development of new chemoprotective agents for cancer.