Abstract
Rubiaceae-type cyclopeptides (RAs) are a type of plant cyclopeptides from the Rubia that have garnered significant attention owing to their unique bicyclic structures and amazing antitumour activities. Our recent work has shown that RAs suppress inflammation and angiogenesis and induce apoptosis. However, the underlying mechanism and targets remained unknown. Nuclear factor κB (NF-κB) signaling pathway plays a critical role in these biological processes, prompting us to investigate whether and how RAs affect this pathway. By screening compound libraries using NF-κB-dependent luciferase reporter, we observed that RA-V is the best NF-κB inhibitor. Further experiments demonstrated that RA-V interrupted the TAK1–TAB2 interaction and targeted TAK1 in this pathway. Moreover, RA-V prevented endotoxin shock and inhibited NF-κB activation and tumor growth in vivo. These findings clarify the mechanism of RA-V on NF-κB pathway and might account for the majority of known bioactivities of RA-V, which will help RA-V develop as new antiinflammatory and antitumour therapies.
Highlights
Natural products derived from medicinal herbs have been a rich source of leading compounds and have played a vital role in drug discovery for centuries[1,2]
We found that Rubiaceae-type cyclopeptides (RAs) were one of potential natural Nuclear factor κB (NF-κB) inhibitors, RA-V (Fig. 1a and Supplementary Figure 1), and observed that RA-V dose-dependently inhibited tumor necrosis factor (TNF)-α-induced activation of an NF-κB-dependent luciferase reporter in HEK293T and HeLa cells
To further confirm the inhibitory activity of RA-V on the NF-κB pathway, we investigated the effect of RA-V on NF-κB target genes by quantitative RT-PCR
Summary
Natural products derived from medicinal herbs have been a rich source of leading compounds and have played a vital role in drug discovery for centuries[1,2]. Rubiaceae-type cyclopeptides (RAs), quinones, and triterpenes have been isolated from the Rubia plants[3,4,5,6]. In the canonical NF-κB pathway the inhibitory protein IκBα is phosphorylated, ubiquitinated and degraded, which leads to the nuclear translocation of the NF-κB complex and regulates the expression of the target genes[12]. Mounting evidence has indicated that the NF-κB signaling pathway plays a critical role in many biological processes and controls the expression of over 500 target genes that are Official journal of the Cell Death Differentiation Association
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