Chen Jie, Wang Yan, Zhao Di, Zhang Lingyuan, Zhang Weimin, Fan Jiawen, Li Jinting, Zhan Qimin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Acta Pharm Sin B. 2021 Jan;11(1):143-155. doi: 10.1016/j.apsb.2020.07.011. Epub 2020 Jul 23.
Among current novel druggable targets, protein-protein interactions (PPIs) are of considerable and growing interest. Diacylglycerol kinase (DGK) interacts with focal adhesion kinase (FAK) band 4.1-ezrin-radixin-moesin (FERM) domain to induce the phosphorylation of FAK Tyr397 site and promotes the malignant progression of esophageal squamous cell carcinoma (ESCC) cells. Chrysin is a multi-functional bioactive flavonoid, and possesses potential anticancer activity, whereas little is known about the anticancer activity and exact molecular mechanisms of chrysin in ESCC treatment. In this study, we found that chrysin significantly disrupted the DGK/FAK signalosome to inhibit FAK-controlled signaling pathways and the malignant progression of ESCC cells both and , whereas produced no toxicity to the normal cells. Molecular validation specifically demonstrated that Asp435 site in the catalytic domain of DGK contributed to chrysin-mediated inhibition of the assembly of DGK/FAK complex. This study has illustrated DGK/FAK complex as a target of chrysin for the first time, and provided a direction for the development of natural products-derived PPIs inhibitors in tumor treatment.
在当前新型可成药靶点中，蛋白质-蛋白质相互作用（PPI）引发了越来越多的关注。二酰基甘油激酶（DGK）与粘着斑激酶（FAK）的带4.1-埃兹蛋白-根蛋白-膜突蛋白（FERM）结构域相互作用，诱导FAK酪氨酸397位点的磷酸化，并促进食管鳞状细胞癌（ESCC）细胞的恶性进展。白杨素是一种多功能生物活性黄酮类化合物，具有潜在的抗癌活性，然而关于白杨素在ESCC治疗中的抗癌活性及确切分子机制却知之甚少。在本研究中，我们发现白杨素显著破坏DGK/FAK信号体，以抑制FAK控制的信号通路及ESCC细胞的恶性进展，且对正常细胞无毒性。分子验证具体表明，DGK催化结构域中的Asp435位点有助于白杨素介导的对DGK/FAK复合物组装的抑制。本研究首次阐明DGK/FAK复合物是白杨素的作用靶点，并为肿瘤治疗中天然产物衍生的PPI抑制剂的开发提供了方向。
