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 the compound inhibits JAK/STAT3 pathway. In this study, we demonstrate for the first time that cucurbitacin B is also a potent inhibitor of NF-kappa B activation. Our results showed that cucurbitacin B inhibited TNF-alpha-induced expression of NF-kappa B reporter gene and NF-kappa B target genes in a dose-dependent manner, however, it did not prevent either stimuli-induced degradation of IkB alpha or nuclear translocation and DNA-binding activity of NF-kappa B. On the other hand, cucurbitacin B dose-dependently suppressed not only NF-kappa B activation induced by overexpression of RelA/p65 but also transactivation activity of RelA/p65 subunit of NF-kappa B. Consistently, treatment of HeLa cells with the compound significantly suppressed TNF-alpha-induced activation of Akt and phosphorylation of Ser536 in RelA/p65, which is required for transactivation activity. Consequently, cucurbitacin B inhibited TNF-alpha-induced expression of NF-kappa B-dependent anti-apoptotic proteins such as c-IAP1, c-IAP2, XIAP, TRAF1, and TRAF2 and sensitized TNF-alpha-induced cell death. Taken together, our results demonstrated that cucurbitacin B could be served as a valuable candidate for the intervention of NF-kappa B-dependent pathological condition such as cancer. J. Cell. Biochem. 112: 1643-1650, 2011. (C) 2011 Wiley-Liss, Inc.