Focal adhesion kinase (FAK) inhibitor-defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network
Focal adhesion kinase (FAK) inhibitor-defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network
复制标题
粘着斑激酶（FAK）抑制剂-defactinib通过有效阻断PI3K/AKT轴和下游分子网络抑制人食管鳞状细胞癌（ESCC）细胞的恶性进展
DOI：
10.1002/mc.23273
复制
发表时间：
2021
影响因子：
4.6
通讯作者：
Chen Jie
中科院分区：
文献类型：
--
作者：
Zhang Lingyuan;Zhao Di;Wang Yan;Zhang Weimin;Zhang Jing;Fan Jiawen;Zhan Qimin;Chen Jie
由于缺乏靶向药物，食管鳞状细胞癌（ESCC）的临床治疗效果不理想。粘着斑激酶（Focal adhesion kinase，FAK）是一种非受体酪氨酸激酶，参与多种肿瘤的发生，近年来被认为是食管鳞癌治疗的重要靶点。在这里，我们发现，defactinib，一个特定的FAK抑制剂，有效地抑制食管鳞癌细胞的恶性。从机制上讲，defactinib剂量和时间依赖性地诱导磷酸肌醇-3-激酶（PI 3 K）从FAK中解离，导致蛋白激酶B（AKT）信号传导阻断，以及通过微阵列和真实的时间聚合酶链反应测定鉴定的几种癌基因（如SOX 2、MYC、EGFR、MET、MDM 2或TGF BR 2）的表达。具体而言，这种FAK抑制介导的PI 3 K/AKT信号传导和下游ESCC特异性生物标志物的抑制在体外实验中维持至24小时，以保证治疗的持久性和有效性。重要的是，defactinib抑制肿瘤生长，转移能力，并增加异种移植动物的总生存期，而不会产生显着的全身毒性。我们的数据表明，FAK抑制提供了一个很好的靶向治疗ESCC有效地抑制PI 3 K/AKT通路和下游分子网络。
The clinical therapeutic efficacy toward esophageal squamous cell carcinoma (ESCC) is undesirable, due to the lack of targeted agents. Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase involved in multiple fields of tumorigenesis, recently has been indicated as a promising therapeutic target in ESCC treatment. Here, we revealed that defactinib, a specific FAK inhibitor, effectively suppressed the malignancy of ESCC cells. Mechanistically, defactinib dose and time‐dependently induced the dissociation of phosphoinositide‐3‐kinase (PI3K) from FAK, resultantly led to blockade of protein kinase B (AKT) signaling, and the expression of several oncogenes, such asSOX2,MYC,EGFR,MET,MDM2, orTGFBR2, identified by microarray and real‐time polymerase chain reaction assay. Specifically, this FAK inhibition‐mediated suppression of PI3K/AKT signaling and downstream ESCC specific biomarkers was maintained to 24 h in in vitro experiments to guarantee the treatment durability and efficacy. Importantly, defactinib suppressed tumor growth, metastatic ability, and increased overall survival of xenografted animals without producing significantly systematic toxicity. Our data suggest that FAK inhibition provides an excellent targeted therapy toward ESCC by effectively inhibiting PI3K/AKT pathway and downstream molecular network.