Aspirin augments the expression of Adenomatous Polyposis Coli protein by suppression of IKKβ

• Published in: Biochemical and biophysical research communications 2014-04, Vol.446 (2), p.460-464
• Main Authors: Ashida, Noboru, Kishihata, Masako, Tien, Dat Nguyen, Kamei, Kaeko, Kimura, Takeshi, Yokode, Masayuki
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ACETYLSALICYLIC ACID; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein - metabolism; ANGIOGENESIS; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aspirin; Aspirin - pharmacology; Cancer; CELL PROLIFERATION; Cells, Cultured; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; GENES; HEK293 Cells; HUMAN POPULATIONS; Humans; I-kappa B Kinase - metabolism; IKKβ; INCUBATION; INFLAMMATION; INHIBITION; NEOPLASMS; NF-kappa B - metabolism; NF-κB; POLYMERASE CHAIN REACTION; PROTEINS; VEINS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.02.134

•Clinical studies revealed aspirin inhibits cancer, but the mechanism is not known.•Adenomatous Polyposis Coli (APC) is a well-known tumor-suppressing gene.•We found aspirin up-regulates the protein of APC.•Aspirin suppressed the expression of IKKβ, an essential kinase in NFκB activation.•The deletion of IKKβ significantly increases the expression of APC protein. Aspirin has been widely used as analgesic, antipyretic and anti-inflammatory medicine for long. In addition to these traditional effects, 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 with Nano-flow LC/MALDI-TOF system. Interestingly, the analysis identified the protein of Adenomatous Polyposis Coli (APC) as one of the most up-regulated protein. APC regulates cell proliferation or angiogenesis, and is widely known as a tumor-suppressing gene which can cause colorectal cancer when it is mutated. Western blots confirmed this result, and real-time PCR indicated it is transcriptionally regulated. We further tried to elucidate the molecular mechanism with focusing on IKKβ. IKKβ is the essential kinase in activation of nuclear factor-kappa B (NF-κB), major transcriptional factors that regulate genes responsible for inflammation or immune response. Previous reports indicated that aspirin specifically inhibits IKKβ activity, and constitutively active form of IKKβ accelerates APC loss. We found that aspirin suppressed the expression of IKKβ, and the deletion of IKKβ by siRNA increases the expression of APC in HEK294 cells. Finally, we observed similar effects of aspirin in human umbilical vein endothelial cells. Taken together, these results reveal that aspirin up-regulates the expression of APC via the suppression of IKKβ. This can be a mechanism how aspirin prevents cancer at least in part, and a novel link between inflammatory NF-κB signaling and cancer.