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An IκBα phosphorylation inhibitor induces heme oxygenase-1(HO-1) expression through the activation of reactive oxygen species (ROS)-Nrf2-ARE signaling and ROS-PI3K/Akt signaling in an NF-κB-independent mechanism

Min, KJ; Lee, JT; Joe, EH; Kwon, TK
Cellular signalling, 23(9):1505-1513, 2011
Journal Title
Cellular signalling
Reactive oxygen species (ROS) are important signaling molecules in cells. Excessive ROS induce expression of inflammatory mediators, such as iNOS and COX2. Antioxidant enzymes, such as, heme oxygenase-1 (HO-1), tightly regulate ROS levels within cells. Here, we show that Bay 11-7082 (Bay) increased HO-1 mRNA and protein expression in human colon cancer HT29 cells. Bay induced translocation of NF-E2-related factor 2 (Nrf2) into nuclei and increased the binding activity of the antioxidant response element (ARE). In addition, PI3K/Akt inhibitor (LY294002) blocked Bay-induced HO-1 expression. Pretreatment with anti-oxidants (N-acetylcysteine (NAC) or glutathione) significantly reduced Bay-induced HO-1 mRNA/protein expression, nuclear translocation of Nrf2 and phosphorylation of Akt. However, PI3K/Akt signaling was independent of Bay-induced Nrf2 translocation and ARE binding activity. Furthermore, other NF-κB inhibitors, such as pyrrolidine dithiocarbamate (PDTC) and MG132, also increased HO-1 mRNA and protein expression. However, although overexpression of dominant negative inhibitory κB (IκB) reduced NF-κB-driven transcriptional activity, IκB overexpression did not increase HO-1 expression. Taken together, our results suggest that in human colon cancer HT29 cells, Bay induces HO-1 expression by increasing ROS production in an Nrf2-ARE and PI3K dependent manner, but Bay acts independently of NF-κB.
MeSH terms
Analysis of VarianceElectrophoretic Mobility Shift AssayGene Expression RegulationGlutathione/pharmacologyHT29 CellsHeme Oxygenase-1/*metabolismHumansImmunohistochemistryLeupeptins/pharmacologyNF-E2-Related Factor 2/metabolismNF-kappa B/antagonists & inhibitorsNitriles/*pharmacologyPhosphatidylinositol 3-Kinases/metabolismPhosphorylationProline/analogs & derivatives/pharmacologyProto-Oncogene Proteins c-akt/metabolismRNA, Messenger/metabolismReactive Oxygen Species/*metabolismResponse Elements*Signal TransductionSulfones/*pharmacologyThiocarbamates/pharmacologyTransfection
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Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
조, 은혜
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