title: Induction of heme oxygenase-1 and inhibition of TPA-induced matrix metalloproteinase-9 expression by andrographolide in MCF-7 human breast cancer cells.
abstract: 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.
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan.
authors.forename: Che-Yi
authors.initials: CY
authors.lastname: Chao
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Hsu
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Lu
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Li
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
mesh_terms: D001663:Bilirubin / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002248:Carbon Monoxide / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004224:Diterpenes / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D004224:Diterpenes; D016328:NF-kappa B; D012333:RNA, Messenger; C030419:andrographolide; D002248:Carbon Monoxide; D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; D001663:Bilirubin