Cis-guggulsterone inhibits the IKK/NF-κB pathway, whereas trans-guggulsterone inhibits MAPK/AP-1 in MCF-7 breast cancer cells: Guggulsterone regulates MMP-9 expression in an isomer-specific manner

Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) are major transcription factors that have been associated with breast cancer metastasis by inducing matrix metallopro-teinase-9 (MMP-9) expression. In this study, we investigated the inhibitory effects of guggulsterone isomers (cis or trans) on 12-O-tetradecanoylpho-bol-13-acetate (TPA)-induced MMP-9 expression. Cis-guggulsterone inhibited TPA-induced MMP expression by blocking IκB kinase (IKK)/NF-κB signaling, whereas trans-guggulsterone blocked mitogen-activated protein kinase (MAPK)/AP-1 signaling. Cis-guggulsterone was more potent than trans-guggulsterone in the inhibition of TPA-induced MMP-9 expression and invasion of MCF-7 cells. Furthermore, we found that the combination of these isomers exerted an additive effect on the inhibition of MCF-7 cell invasion. These results suggest that guggulsterone isomers downregulate MMP-9 expression and tumor cell invasion through the isomer-specific suppression of IKK/NF-κB and MAPK/AP-1 activation. In addition, the suppression of MMP-9 expression correlated well with the inhibition of cell invasion.