Chrysin serves as a novel inhibitor of DGKα/FAK interaction to suppress the malignancy of esophageal squamous cell carcinoma (ESCC).
Chrysin serves as a novel inhibitor of DGKα/FAK interaction to suppress the malignancy of esophageal squamous cell carcinoma (ESCC).
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白杨素作为 DGK α/FAK 相互作用的新型抑制剂，可抑制食管鳞状细胞癌 (ESCC) 的恶性肿瘤
DOI：
10.1016/j.apsb.2020.07.011
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Zhan Q
中科院分区：
文献类型：
--
作者：
Chen J;Wang Y;Zhao D;Zhang L;Zhang W;Fan J;Li J;Zhan Q
在目前的新型药物靶点中，蛋白质-蛋白质相互作用（PPI）引起了相当大的兴趣。二酰基甘油激酶α（DGKα）与粘着斑激酶（FAK）带4.1-ezrin-radixin-moesin（FERM）结构域相互作用，诱导FAK Tyr 397位点磷酸化，促进食管鳞状细胞癌（ESCC）细胞恶性进展。白杨素是一种具有多种生物活性的黄酮类化合物，具有潜在的抗癌活性，但白杨素在食管鳞癌治疗中的抗癌活性及其确切的分子机制尚不清楚。本研究发现白杨素在体内外均能显著阻断DGKα/FAK信号体，抑制FAK信号通路，抑制ESCC细胞恶性进展，而对正常细胞无毒性作用。分子生物学验证表明，DGKα催化结构域中的Asp 435位点参与了白杨素介导的DGKα/FAK复合物组装的抑制作用。本研究首次阐明DGKα/FAK复合物是白杨素的作用靶点，为开发天然产物来源的PPI抑制剂用于肿瘤治疗提供了方向。在食管鳞癌细胞中，Escherin通过与二酰基甘油激酶α（DGK α）的Asp 435位点相互作用，破坏DGK α/FAK信号体的组装，进而抑制FAK/AKT通路的激活，从而介导其抗肿瘤作用。
Among current novel druggable targets, protein–protein interactions (PPIs) are of considerable and growing interest. Diacylglycerol kinase α (DGKα) 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 DGKα/FAK signalosome to inhibit FAK-controlled signaling pathways and the malignant progression of ESCC cells both in vitro and in vivo, whereas produced no toxicity to the normal cells. Molecular validation specifically demonstrated that Asp435 site in the catalytic domain of DGKα contributed to chrysin-mediated inhibition of the assembly of DGKα/FAK complex. This study has illustrated DGKα/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. Chrysin disrupted the assembly of diacylglycerol kinase α (DGKα)/focal adhesion kinase (FAK) signalosome via interacting with the Asp 435 site of DGKα and subsequently inhibited the activation of FAK/AKT pathway to mediate its antitumor effect in esophageal squamous cell carcinoma cells.
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影响因子：
9
作者：
Cao J;Lv W;Wang L;Xu J;Yuan P;Huang S;He Z;Hu J
通讯作者：
Hu J
细胞质LIF重新编程可通过调节YAP1-FAK/PXN信号传导来增强NPC传播。
影响因子：
16.6
作者：
Liu SC;Hsu T;Chang YS;Chung AK;Jiang SS;OuYang CN;Yuh CH;Hsueh C;Liu YP;Tsang NM
通讯作者：
Tsang NM
影响因子：
11.2
作者：
Hu N;Kadota M;Liu H;Abnet CC;Su H;Wu H;Freedman ND;Yang HH;Wang C;Yan C;Wang L;Gere S;Hutchinson A;Song G;Wang Y;Ding T;Qiao YL;Koshiol J;Dawsey SM;Giffen C;Goldstein AM;Taylor PR;Lee MP
通讯作者：
Lee MP
DOI：
10.1038/nrc3792
发表时间：
2014-09
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.6
作者：
Khoo BY;Chua SL;Balaram P
通讯作者：
Balaram P