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

Pei Ming Yang, Wei Chien Huang, Yi Chu Lin, Wen Yu Huang, Hui Ann Wu, Wei Lun Chen, Yu Fan Chang, Chia Wei Chou, Cherng Chyi Tzeng, Yeh Long Chen, Ching Chow Chen

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)687-698
Number of pages12
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number3
DOIs
Publication statusPublished - Mar 2010
Externally publishedYes

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Keywords

  • IKKβ
  • P21
  • P53

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

Yang, P. M., Huang, W. C., Lin, Y. C., Huang, W. Y., Wu, H. A., Chen, W. L., Chang, Y. F., Chou, C. W., Tzeng, C. C., Chen, Y. L., & Chen, C. C. (2010). Loss of IKKβ activity increases p53 stability and p21 expression leading to cell cycle arrest and apoptosis. Journal of Cellular and Molecular Medicine, 14(3), 687-698. https://doi.org/10.1111/j.1582-4934.2009.00712.x