Loss of IKKbeta activity increases p53 stability and p21 expression leading to cell cycle arrest and apoptosis.
Elevated levels of NF-kappaB are frequently detected in many inflammatory diseases and cancers. Blocking the IKK-NF-kappaB pathway has been seen as a promising approach for new therapies. By employing the dominant-negative mutant of IKKbeta, our data revealed that loss of IKKbeta 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 IKKbeta inhibitors (CYL-19s and CYL-26z) leads to the arrest of cell cycle progression at G1 and G2/M, followed by apoptosis. IKKbeta inhibitors can increase the protein stability, nuclear accumulation and promoter-binding activity of p53, leading to the p21 gene transcription. Furthermore, knockdown of IKKbeta by siRNA increased the stability and expression of p53 and p21 promoter activity. In addition, IKKbeta inhibitor-induced p53 and p21 expressions were augmented in the presence of IKKbeta siRNA. Correlation between p53 acetylation and its protein stabilization was also seen after treatment with IKKbeta inhibitors. These results suggest that loss of IKKbeta activation is important for the enhancement of p53 stability, leading to p21 expression and cell cycle arrest and apoptosis of tumour cells.
Yang
Pei-Ming
PM
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Huang
Wei-Chien
WC
Lin
Yi-Chu
YC
Huang
Wen-Yu
WY
Wu
Hui-Ann
HA
Chen
Wei-Lun
WL
Chang
Yu-Fan
YF
Chou
Chia-Wei
CW
Tzeng
Cherng-Chyi
CC
Chen
Yeh-Long
YL
Chen
Ching-Chow
CC
D000166:Acridines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005663:Furans / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C504217:5-(4-acridin-9-ylamino)phenyl-5-methyl-3-methylenedihydrofuran-2-one; D000166:Acridines; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005663:Furans; D016159:Tumor Suppressor Protein p53; D051550:I-kappa B Kinase; C496560:IKBKB protein, human