Journal Article

Roburic Acid Targets TNF to Inhibit the NF-κB Signaling Pathway and Suppress Human Colorectal Cancer Cell Growth

Chen, Fei, Xu, Jing, Xu, Huanhuan, Liu, Titi, Wang, Xuanjun, Jiang, Li, Xiang, Zemin, Sheng, Jun, Li, Jin, Hu, Lihong

2022

Overview

Tumor necrosis factor (TNF)-stimulated nuclear factor-kappa B (NF-κB) signaling plays very crucial roles in cancer development and progression, and represents a potential target for drug discovery. Roburic acid is a newly discovered tetracyclic triterpene acid isolated from oak galls and exhibits anti-inflammatory activity. However, whether roburic acid exerts antitumor effects through inhibition of TNF-induced NF-κB signaling remains unknown. Here, we demonstrated that roburic acid bound directly to TNF with high affinity ( K D = 7.066 μM), blocked the interaction between TNF and its receptor (TNF-R1), and significantly inhibited TNF-induced NF-κB activation. Roburic acid exhibited antitumor activity in numerous cancer cells and could effectively induce G0/G1 cell cycle arrest and apoptosis in colorectal cancer cells. Importantly, roburic acid inhibited the TNF-induced phosphorylation of IKKα/β, IκBα, and p65, degradation of IκBα, nuclear translocation of p65, and NF-κB-target gene expression, including that of XIAP, Mcl-1, and Survivin, in colorectal cancer cells. Moreover, roburic acid suppressed tumor growth by blocking NF-κB signaling in a xenograft nude mouse model of colorectal cancer. Taken together, our findings showed that roburic acid directly binds to TNF with high affinity, thereby disrupting its interaction with TNF-R1 and leading to the inhibition of the NF-κB signaling pathway, both in vitro and in vivo . The results indicated that roburic acid is a novel TNF-targeting therapeutics agent in colorectal cancer as well as other cancer types.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acids / Animals / Anti-inflammatory agents / Antibodies / Antitumor activity / Apoptosis / Biotechnology / Cancer / Cancer therapies / Cell cycle / Cell growth / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Gene expression / Humans / Immunology / Mcl-1 protein / Mice / NF-kappa B - metabolism / NF-KappaB Inhibitor alpha - metabolism / NF-κB protein / NF-κB signaling / Nuclear transport / Phosphorylation / Proteins / Receptors, Tumor Necrosis Factor, Type I / roburic acid / Signal Transduction / Software / Survivin / TNF / TNF-R1 / Tumor necrosis factor / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-TNF / XIAP protein