Cucurbitacin B Suppresses The Transactivation Activity of RelA/p65

Cucurbitacin B, a natural triterpenoid is well known for its strong anticancer activity, and recent studies showed that cucurbitacicn B inhibits JAK/STAT3 pathway. In this study, we demonstrate for the first time that cucurbitacin B is also a potent inhibitor of NF‐κB activation. Our results showed that cucurbitacin B inhibited TNF‐α‐induced expression of NF‐κB reporter gene and NF‐κB target genes in a dose‐dependent manner, however, cucurbitacin B did not prevent either stimuli‐induced degradation of IκBα or nuclear translocation and DNA‐binding activity of NF‐κB. On the other hand, cucurbitacin B dose‐dependently suppressed not only NF‐κB activation induced by overexpression of RelA/p65 but also transactivation activity of RelA/p65 subunit of NF‐κB. Consistently, treatment of HeLa cells with cucurbitacin B significantly suppressed TNF‐α‐induced activation of Akt and phosphorylation of Ser536 in RelA/p65, which is required for transactivation activity. Consequently, cucurbitacin B inhibited TNF‐α‐induced expression of NF‐κB dependent anti‐apoptotic proteins such as c‐IAP1, c‐IAP2, XIAP, TRAF1, and TRAF2 and sensitized TNF‐α‐induced cell death. Taken together, our results demonstrated that cucurbitacin B could be served as a valuable candidate for the intervention of NF‐κB‐dependent pathological condition such as cancer.