Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan.
Carcinogenesis. 2013 Aug;34(8):1843-51. doi: 10.1093/carcin/bgt131. Epub 2013 Apr 24.
Matrix metalloproteinase-9 (MMP-9) plays a critical role in cancer metastasis. Andrographolide (AP) is a diterpene lactone in the leaves and stem of Andrographis paniculata (Burm. f) Ness that has been reported to possess anticancer 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 dose-dependently inhibited TPA-induced MMP-9 protein expression, enzyme activity, migration and invasion. In addition, AP significantly induced heme oxygenase-1 (HO-1) messenger RNA (mRNA) and protein expression. Transfection with HO-1 small interfering RNA knocked down the HO-1 expression and reversed the inhibition of MMP-9 expression by AP. HO-1 end products, such as carbon monoxide, free iron and bilirubin, suppressed the TPA-induced MMP-9 mRNA and protein expression, enzyme activity, migration and invasion in MCF-7 cells. Furthermore, TPA-induced extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation and the DNA binding activity of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) were attenuated by pretreatment with AP and HO-1 end products. In conclusion, these results suggest that AP inhibits TPA-induced cell migration and invasion by reducing MMP-9 activation, which is mediated mainly by inhibition of the ERK1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways and subsequent AP-1 and NF-κB transactivation. Additionally, induction of HO-1 expression is at least partially involved in the inhibition of TPA-induced MMP-9 activation and cell migration in MCF-7 cells by AP.
基质金属蛋白酶-9（MMP-9）在癌症转移中发挥着关键作用。穿心莲内酯（AP）是穿心莲（Burm. f）Ness 的叶子和茎中的二萜内酯，已被报道具有抗癌活性。在这项研究中，我们研究了 AP 对 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的 MCF-7 乳腺癌细胞 MMP-9 表达和侵袭的影响及其可能的机制。结果表明，AP 呈剂量依赖性抑制 TPA 诱导的 MMP-9 蛋白表达、酶活性、迁移和侵袭。此外，AP 显著诱导血红素加氧酶-1（HO-1）信使 RNA（mRNA）和蛋白表达。HO-1 小干扰 RNA 的转染敲低了 HO-1 的表达，并逆转了 AP 对 MMP-9 表达的抑制。HO-1 的终产物，如一氧化碳、游离铁和胆红素，抑制了 TPA 诱导的 MMP-9 mRNA 和蛋白表达、酶活性、迁移和侵袭。此外，AP 和 HO-1 终产物预处理可减弱 TPA 诱导的细胞外信号调节激酶（ERK）1/2 和 Akt 磷酸化以及激活蛋白-1（AP-1）和核因子-κB（NF-κB）的 DNA 结合活性。总之，这些结果表明，AP 通过减少 MMP-9 的激活来抑制 TPA 诱导的细胞迁移和侵袭，这主要是通过抑制 ERK1/2 和磷脂酰肌醇 3-激酶/Akt 信号通路以及随后的 AP-1 和 NF-κB 反式激活来介导的。此外，HO-1 表达的诱导至少部分参与了 AP 抑制 TPA 诱导的 MMP-9 激活和 MCF-7 细胞迁移。
