Triptolidenol, isolated from Tripterygium wilfordii, disrupted NF-κB/COX-2 pathway by targeting ATP-binding sites of IKKβ in clear cell renal cell carcinoma.

Triptolidenol (TPD) is an epoxy diterpene lactone from Tripterygium wilfordii, which has been used for chronic nephritis in China，and possessed various pharmacological properties, such as anti-inflammatory and anti-cancer activities. However, the precise molecular antitumor mechanism of TPD remains to be elucidated. In this study, we investigated the effects of TPD on human clear cell renal cell carcinoma (ccRCC) and investigated its precise anti-tumor mechanisms. It was showed that TPD significantly suppressed ccRCC cell proliferation, cell migration, and induced cell cycle arrest at S phase. Furthermore, TPD also induced apoptosis by activating the cytochrome c (cyt c)/caspase cascade signaling pathway. Moreover, using confocal immunofluorescence, a dual-luciferase reporter assay and molecular docking study, the results showed that TPD obviously reduced the expression of COX-2 by inhibiting the kinase activity of IKKβ via targeting its ATP-binding domain, and then attenuating the transactivation of NF-κB. Collectively, our study demonstrated that TPD suppressed renal cell carcinoma growth through disrupting NF-κB/COX-2 pathway by targeting ATP-binding sites of IKKβ, and provided pharmacological evidence that TPD exhibits potential use in the treatment of COX-2-mediated diseases such as ccRCC.