穿心蓮內酯誘發血基質氧化酶-1與抑制TPA誘發基質金屬蛋白酶-9表現關係之探討

Abstract

Matrix metalloproteinase-9 (MMP-9) plays a critical role in cancer metastasis. Andrographolide (AP) has been reported to possess anti-cancer activity. In this study, we investigated the effect of AP on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 expression and invasion in MCF-7 breast cancer cells and the possible mechanisms involved. The results showed that AP inhibited TPA-induced MMP-9 expression, enzyme activity, migration and invasion in a dose-dependent manner. In addition, AP significantly induced HO-1 mRNA and protein expression. Transfection with HO-1 siRNA knocked down HO-1 expression and reversed the AP inhibition of MMP-9 expression. HO-1 end products, RuCO, FeCl3, and bilirubin suppressed TPA-induced MMP-9 expression, enzyme activity, migration and invasion in MCF-7 cells. Furthermore, TPA-induced ERK1/2 and Akt phosphorylation, AP-1 and NF-κB DNA binding activity were attenuated by pretreatment with AP. Moreover, results of tube formation assay and chorioallantoic membrane (CAM) assay revealed that AP suppressed in vitro and ex vivo angiogenesis. In conclusion, these results suggested that AP inhibits TPA-induced cell migration and invasion by reducing MMP-9 activation, mainly mediated by inhibition of ERK1/2 and PI3K/Akt signaling pathways and subsequently AP-1 and NF-κB trans-activation. Additionally, induction of HO-1 expression is at least partially involved in the inhibition of TPA-induced MMP-9 activation by AP in MCF-7 cells.