Inhibition of IKK activity enhances cell cycle arrest through p53-dependent p21^Cip/WAF1 activation. Free

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Elevated levels of NF-κB are frequently detected in many inflammatory diseases and cancer. 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 IKK activity reduces not only the proliferation and invasion of lung adenocarcinoma A549 cells in vitro, but also the tumor formation, metastasis and angiogenesis in mouse xenograft model. The treatment of IKK inhibitors also led to the arrest of cell cycle progression at G1/S transition due to the enhancement of p21^Cip/WAF1 expression in a p53-dependnet manner. Without affecting the mRNA level of p53, IKK inhibitors can increase the protein stability, nuclear accumulation, and promoter-binding activity of p53, thereby led to the p21^Cip/WAF1 gene transcription. Furthermore, the correlation between the acetylation of p53 and its protein stabilization was also seen in the IKK inhibitor-treated A549 cells, indicating the involvement of the cross-talk among IKK, acetyltransferase, and p53. These results provide a new insight into the molecular mechanism other than NF-κB inhibition by IKK inhibitors to cause the arrest of tumor cell proliferation.