Title: Bid mediates anti-apoptotic COX-2 induction through the IKKbeta/NFkappaB pathway due to 5-MCDE exposure.
Authors: Luo, Wenjing; Li, Jingxia; Zhang, Dongyun; Cai, T; Song, Lun; Yin, Xiao-Ming; Desai, Dhimant; Amin, Shantu; Chen, Jingyuan; Huang, Chuanshu
Published In Curr Cancer Drug Targets, (2010 Feb)
Abstract: Although Bid has been considered as a cell apoptotic mediator, current studies suggest a possible role in cell survival in mouse embryonic fibroblasts (MEFs) response to low doses of anti-(+/-)-5- methylchrysene-1,2-diol-3,4-epoxide(<or=0.25 microM) (5-MCDE). We found that exposure of MEFs to 0.25 microM 5-MCDE resulted in a slight apoptotic induction, while this apoptotic response was substantially increased in the Bid knockout MEFs (Bid(-/-)), suggesting Bid-mediated anti-apoptotic function in this response. This notion was further supported by the findings that re-constitution expression of Bid into Bid(-/-) cells could inhibit the increased apoptosis. Further studies showed that Bid anti-apoptotic function was associated with its mediation of COX-2 expression, which was based on the results of the reduction of COX-2 expression in Bid(-/-) cells, restoration of low sensitivity to 5-MCDE apoptotic response by the introduction of Bid into Bid(-/-) cells and increased sensitivity of WT MEFs to 5-MCDE apoptosis by knockdown of COX-2 expression. Furthermore, Bid mediated COX-2 expression through the IKKbeta/NFkappaB pathway because the deficiency of Bid in Bid(-/-) MEFs resulted in blockade of IKK/NFkappaB activation and knockout of IKKbeta caused abrogation of COX-2 expression induced by 5-MCDE. Collectively, our results demonstrate that Bid is critical for COX-2 induction through the IKKbeta/NFkappaB pathway, which mediates its anti-apoptotic function, in cell response to low doses of 5-MCDE exposure.
PubMed ID: 20088789
MeSH Terms: Animals; Apoptosis*; BH3 Interacting Domain Death Agonist Protein/metabolism*; Carcinogens/toxicity*; Cells, Cultured; Chrysenes/toxicity*; Cyclooxygenase 2/metabolism*; Fibroblasts/drug effects; Fibroblasts/metabolism; I-kappa B Kinase/metabolism*; Mice; NF-kappa B/metabolism*