Qi Yonghao, Zhao Xuan, Chen Jiaying, Pradipta Ambara R, Wei Jing, Ruan Haihua, Zhou Lijun, Hsung Richard P, Tanaka Katsunori
a Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology , Tianjin University , Tianjin , P.R. China.
b Biofunctional Synthetic Chemistry Laboratory , RIKEN , Wako, Saitama , Japan.
Biosci Biotechnol Biochem. 2019 Jun;83(6):1011-1026. doi: 10.1080/09168451.2018.1559030. Epub 2018 Dec 20.
TRAF6 is highly expressed in many tumors and plays an important role in the immune system. The aim of this study is to confirm anti-tumor activities of all naturally occurring Cinchona alkaloids that have been screened using computational docking program, and to validate the accuracy and specificity of the RING domain of TRAF6 as a potential anti-tumor target, and to explore their effect on the immune system. Results reported herein would demonstrate that Cinchona alkaloids could induce apoptosis in HeLa cells, inhibit the ubiquitination and phosphorylation of both AKT and TAK1, and up-regulate the ratio of Bax/Bcl-2. In addition, these compounds could induce apoptosis in vivo, and increase the secretion of TNF-α, IFN-γ, and IgG, while not significantly impacting the ratio of CD4T/CD8T. These investigations suggest that the RING domain of TRAF6 could serve as a de novo biological target for therapeutic treatment in cancers.
TRAF6在许多肿瘤中高表达，并在免疫系统中发挥重要作用。本研究的目的是确认使用计算对接程序筛选出的所有天然金鸡纳生物碱的抗肿瘤活性，验证TRAF6的RING结构域作为潜在抗肿瘤靶点的准确性和特异性，并探索它们对免疫系统的影响。本文报道的结果将证明金鸡纳生物碱可诱导HeLa细胞凋亡，抑制AKT和TAK1的泛素化和磷酸化，并上调Bax/Bcl-2的比率。此外，这些化合物可在体内诱导凋亡，并增加TNF-α、IFN-γ和IgG的分泌，同时对CD4T/CD8T的比率没有显著影响。这些研究表明，TRAF6的RING结构域可作为癌症治疗的全新生物学靶点。
