Inhibition of protein FAK enhances 5-FU chemosensitivity to gastric carcinoma via p53 signaling pathways
Inhibition of protein FAK enhances 5-FU chemosensitivity to gastric carcinoma via p53 signaling pathways
复制标题
抑制FAK蛋白通过p53信号通路增强5-FU对胃癌的化疗敏感性
DOI：
10.1016/j.csbj.2019.12.010
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发表时间：
2020-01-01
影响因子：
6
通讯作者：
Yu, Yongsheng
中科院分区：
文献类型：
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作者：
Hou, Jingjing;Tan, Yuyu;Yu, Yongsheng
小分子药物5-氟尿嘧啶（5-FU）广泛应用于胃癌（GC）的治疗，但疗效不佳，且存在获得性和内在耐药。粘着斑激酶（Focal adhesion kinase，FAK）是一种非受体酪氨酸激酶，在胃癌细胞的粘附、迁移和增殖中起重要作用，有望成为胃癌治疗的新靶点。采用RT-qPCR和TCGA数据库分析法检测胃癌组织中FAK的差异表达。为了研究FAK的生物学功能，进行了功能丧失实验。采用CCK-8法、集落形成法、流式细胞术、双荧光素酶报告基因法和蛋白质印迹法研究FAK在胃癌5-FU化疗敏感性中的作用机制。胃癌患者中FAK过表达，且与预后不良呈正相关。在体外，使用shRNA干扰靶向FAK降低GC细胞的增殖并增加其凋亡。重要的是，FAK沉默增强了5-FU的治疗效果，导致体内肿瘤生长减少。我们进一步证明FAK沉默增加5-FU诱导的caspase-3活性，并促进p53转录活性。临床数据还显示，FAK水平较高的患者的总生存期（OS）和首次进展时间（FP）显著短于FAK水平较低的患者。这些结果表明，FAK在GC的5-FU化疗敏感性中起着关键作用，使用FAK抑制剂作为5-FU的辅助治疗可能是接受化疗的患者的有效策略。(C)2019作者由Elsevier B. V.代表计算和结构生物技术研究网络出版。
The small molecule drug 5-fluorouracil (5-FU) is widely used in the treatment for gastric cancer (GC), however, it exerts poor efficacy and is associated with acquired and intrinsic resistance. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a key role in adhesion, migration, and proliferation of gastric carcinoma cells, suggesting that this kinase may be a promising therapeutic target. Differentially expressed FAK in GC tissue was detected by RT-qPCR and TCGA database analysis. To investigate the biological functions of FAK, loss-of-function experiments were performed. CCK-8 assay, colony formation assay, flow cytometry, dual-luciferase reporter assays, and western blot assays were conducted to determine the underlying mechanisms of FAK in 5-FU chemosensitivity in GC. FAK is overexpressed in GC patients, and positively correlated with poor prognosis. The use of shRNA interference to target FAK decreased proliferation and increased apoptosis of GC cells in vitro. Importantly, FAK silencing enhanced the therapeutic efficacy of 5-FU, leading to reduced tumor growth in vivo. We further demonstrated that FAK silencing increased 5-FU-induced caspase-3 activity, and promoted p53 transcriptional activities. Clinical data also has shown that patients with higher levels of FAK had significantly shorter overall survival (OS) and time to first progression (FP) than those with lower levels of FAK. These findings indicate that FAK plays a critical role in 5-FU chemosensitivity in GC, and the use of FAK inhibitors as an adjunct to 5-FU might be an effective strategy for patients who undergo chemotherapy. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.