Bid Mediates Anti-Apoptotic COX-2 Induction Through the IKKβ/NFκB Pathway Due to 5-MCDE Exposure

Although Bid is considered to be a cell apoptotic mediator, current studies suggest that it has a possible role in cell survival for mouse embryonic fibroblasts (MEFs) in response to low doses of anti-(+/-)-5-methylchrysene-1,2-diol-3,4-epoxide (<= 0.25 mu M) (5-MCDE). We found that the exposure of MEFs to 0.25 mu M 5-MCDE resulted in a slight apoptotic induction, while this apoptotic response was substantially increased in the Bid knockout MEFs (Bid(-/-)), suggesting that there is a 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 show that the antiapoptotic function of Bid was associated with its mediation of COX-2 expression. This conclusion was based the reduction of COX-2 expression in Bid(-/-) cells, the restoration of low sensitivity to 5-MCDE-induced apoptosis by the introduction of Bid into Bid(-/-) cells, and increased sensitivity of WT MEFs to 5-MCDE-induced apoptosis by the knockdown of COX-2 expression. Furthermore, we found that Bid mediated COX-2 expression through the IKK beta/NF kappa B pathway because the deficiency of Bid in Bid(-/-) MEFs resulted in the blockade of IKK beta/NF kappa B activation and knockout of IKK beta caused abrogation of COX-2 expression induced by 5-MCDE. Collectively, our results demonstrate that Bid is critical for COX-2 induction through the IKK beta/NF kappa B pathway, which mediates its anti-apoptotic function, in cell response to low doses of 5-MCDE exposure.