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

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.