Study on the negative regulators of IKKβ/NF-κB focusing on the link between inflammation and cancer

炎症と癌の関連に注目した IKKβ/NF-κ抑制メカニズムの研究

2014-09-25

2014-09-25

NF-kB is a major transcriptional factor regulating many cellular functions including inflammation; and its role is a pivotal link between inflammation an cancer. Therefore, its appropriate control is of high importance. In this study, we showed a novel negative regulator of IKKb, an essential kinase in NF-kB signaling; and a novel mechanism in that an anti-inflammatory medicine, aspirin protects against cancer via IKKb/NF-kB. First, AMAP1 was showed as a negative feedback regulator for NF-kB by binding with IKKb. Proteomics analysis identified AMAP1 as a binding protein with IKKb. Overexpression of AMAP1 suppressed NF-kB activity by interfering the binding of IKKb and NEMO, and deletion of AMAP1 augmented NF-kB activity. The activation of NF-kB induced translocation of AMAP1 to cytoplasm from cell membrane and nucleus, which resulted in augmented interaction of AMAP1 and IKKb. These results demonstrated a advanced role of AMAP1 as a negative feedback regulator of NF-kB, and presented it as a possible target for anti-inflammatory treatments. Second, clinical studies suggest that aspirin can protect against cancer, but its mechanism has not been explored. To unveil it, we identified the proteins up- or down-regulated after incubation with aspirin by using proteomics analysis. Interestingly, the analysis identified APC as one of the most up-regulated protein. APC regulates cell proliferation or angiogenesis, and is widely known as a tumorsuppressing gene which can cause colorectal cancer when it is mutated. Previous reports indicated that aspirin specifically inhibits IKKb activity, and constitutively active form of IKKb accelerates APC loss. We found that aspirin suppressed the expression of IKKb, and the deletion of IKKb by siRNA increases the expression of APC in HEK294 cells and HUVECs. These results reveal that aspirin up-regulates the expression of APC via the suppression of IKKb, which can be a mechanism how aspirin prevents cancer at least in part.

博士(学術)

京都工芸繊維大学

14303甲第718号

http://hdl.handle.net/10212/2192

en

ETD

Thesis or Dissertation

Thesis