Loss of IKKβ activity increases p53 stability and p21 expression leading to cell cycle arrest and apoptosis

Elevated levels of NF-κB are frequently detected in many inflammatory diseases and cancers. Blocking the IKK-NF-κB pathway has been seen as a promising approach for new therapies. By employing the dominant-negative mutant of IKKβ, our data revealed that loss of IKKβ activity reduces not only the proliferation and invasion of lung adenocarcinoma A549 cells in vitro but also the tumour formation, metastasis and angiogenesis in mouse xenograft model. Treatment of IKKβ inhibitors (CYL-19s and CYL-26z) leads to the arrest of cell cycle progression at G1 and G2/M, followed by apoptosis. IKKβ inhibitors can increase the protein stability, nuclear accumulation and promoter-binding activity of p53, leading to the p21 gene transcription. Furthermore, knockdown of IKKβ by siRNA increased the stability and expression of p53 and p21 promoter activity. In addition, IKKβ inhibitor-induced p53 and p21 expressions were augmented in the presence of IKKβ siRNA. Correlation between p53 acetylation and its protein stabilization was also seen after treatment with IKKβ inhibitors. These results suggest that loss of IKKβ activation is important for the enhancement of p53 stability, leading to p21 expression and cell cycle arrest and apoptosis of tumour cells. ? 2009 The Authors Journal compilation ? 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.