Cordycepin suppresses TNF-α-induced NF-κB activation by reducing p65 transcriptional activity, inhibiting IκBα phosphorylation, and blocking IKKγ ubiquitination

• Published in: International immunopharmacology 2012-12, Vol.14 (4), p.698-703
• Main Authors: Ren, Zhenghua, Cui, Jianhua, Huo, Zeren, Xue, Jinru, Cui, Hao, Luo, Bin, Jiang, Lanjin, Yang, Rirong
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cordycepin; Deoxyadenosines - administration & dosage; Deoxyadenosines - pharmacology; Dose-Response Relationship, Drug; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; I-kappa B Kinase - metabolism; I-kappa B Proteins - metabolism; IKK; IκB; Medical sciences; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; NF-κB; Pharmacology. Drug treatments; Phosphorylation; Plasmids; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Ubiquitination
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2012.10.008

Cordycepin is reported to participate in multiple pharmacological activities including anti-tumor and anti-inflammation, and is involved in the regulation of NF-κB signaling pathway. However, the detailed molecular mechanism of cordycepin in suppression of NF-κB signaling pathway remains ambiguous. In this study, we first analyzed the effect of cordycepin on NF-κB activity in HEK-293T cells, and found that cordycepin resulted in a dose-dependent reduction in TNF-α-induced NF-κB activation. Although cordycepin did not block TNF-α-induced nuclear translocation of p65, high concentration of cordycepin reduced the DNA-binding and transcriptional activities of NF-κB. Moreover, cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα. Further investigation revealed that cordycepin suppressed IKKs-mediated NF-κB activation and inhibited the ubiquitination of IKKγ. In conclusion, cordycepin effectively inhibits NF-κB signaling through suppressing the activities of NF-κB, IκB and IKK. Thus, cordycepin may provide some potential therapeutic application in inflammation-associated disorders and cancer. ► Cordycepin resulted in a dose-dependent reduction in TNF-α-induced NF-κB activation. ► Cordycepin reduced p65 transcriptional activity at high concentration. ► Cordycepin inhibited IκBα phosphorylation. ► Cordycepin inhibited IKKs-mediated NF-κB activation. ► Cordycepin suppressed IKKγ ubiquitination in a dose-dependent manner.