Center for Molecular Cancer Research, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk 363-883, Republic of Korea.
J Cell Biochem. 2011 Jun;112(6):1643-50. doi: 10.1002/jcb.23078.
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-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, it 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 the compound 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.
葫芦素 B 是一种天然三萜类化合物，以其强大的抗癌活性而闻名，最近的研究表明该化合物抑制 JAK/STAT3 通路。在这项研究中，我们首次证明葫芦素 B 也是 NF-κB 激活的有效抑制剂。我们的结果表明，葫芦素 B 以剂量依赖的方式抑制 TNF-α诱导的 NF-κB 报告基因和 NF-κB 靶基因的表达，但它既不能阻止刺激诱导的 IκBα降解，也不能阻止 NF-κB 的核转位和 DNA 结合活性。另一方面，葫芦素 B 以剂量依赖的方式不仅抑制了 RelA/p65 过表达诱导的 NF-κB 激活，还抑制了 NF-κB 的 RelA/p65 亚基的转录激活活性。一致地，用该化合物处理 HeLa 细胞显著抑制了 TNF-α诱导的 Akt 的激活和 RelA/p65 的 Ser536 磷酸化，这是转录激活活性所必需的。因此，葫芦素 B 抑制了 TNF-α诱导的 NF-κB 依赖性抗凋亡蛋白如 c-IAP1、c-IAP2、XIAP、TRAF1 和 TRAF2 的表达，并使 TNF-α诱导的细胞死亡敏感化。总之，我们的结果表明，葫芦素 B 可以作为干预 NF-κB 依赖性病理状况（如癌症）的有价值的候选药物。
