CK2 inhibitor CX-4945 blocks TGF-β1-induced epithelial-to-mesenchymal transition in A549 human lung adenocarcinoma cells.
CK2 inhibitor CX-4945 blocks TGF-β1-induced epithelial-to-mesenchymal transition in A549 human lung adenocarcinoma cells.
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DOI：
10.1371/journal.pone.0074342
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hwan Kim S
中科院分区：
文献类型：
--
作者：
Kim J;Hwan Kim S
上皮-间质转化（EMT）是肿瘤转移和侵袭的主要表型。蛋白激酶CK 2（casein kinase 2）作为一种可药物化的肿瘤靶点，其抑制作用已被认为是治疗EMT控制的肿瘤转移的一种有前景的治疗策略。本研究旨在评估CK 2抑制剂CX-4945对A549人肺腺癌细胞EMT过程中癌细胞迁移和侵袭过程的影响。在用TGF-β1（5 ng/ml）和CX-4945处理的A549细胞中评价CX-4945对TGF-β1诱导的EMT的影响。通过Western blot、免疫细胞化学和报告基因分析研究CX-4945对TGF-β1诱导的cadherin开关以及Smad、non-Smad、Wnt和黏着斑信号通路中关键信号分子激活的影响。此外，通过伤口愈合实验、Boyden小室实验、明胶酶谱和实时荧光定量PCR研究CX-4945对TGF-β1诱导的细胞迁移和侵袭的影响。CX-4945抑制TGF-β1诱导的钙粘蛋白开关以及参与Smad（Smad 2/3、Twist和Snail）、非Smad（Akt和Erk）、Wnt（β-catenin）和粘着斑信号通路（FAK、Src和paxillin）的关键信号分子的激活，这些信号通路协同调节EMT的整个过程。CX-4945抑制A549细胞的迁移和侵袭，同时下调MMP-2和MMP-9的表达。CX-4945在人体中作为实体瘤和多发性骨髓瘤单药治疗的临床评价已确立其具有前景的药代动力学、药效学和安全性特征。除了肿瘤质量的消退，CX-4945可能是癌症转移和EMT相关疾病的新疗法。
The epithelial-to-mesenchymal transition (EMT) is a major phenotype of cancer metastasis and invasion. As a druggable cancer target, the inhibition of protein kinase CK2 (formally named to casein kinase 2) has been suggested as a promising therapeutic strategy to treat EMT-controlled cancer metastasis. This study aimed to evaluate the effect of the CK2 inhibitor CX-4945 on the processes of cancer migration and invasion during the EMT in A549 human lung adenocarcinoma cells. The effect of CX-4945 on TGF-β1-induced EMT was evaluated in A549 cells treated with TGF-β1 (5 ng/ml) and CX-4945. The effect of CX-4945 on TGF-β1-induced cadherin switch and activation of key signaling molecules involved in Smad, non-Smad, Wnt and focal adhesion signaling pathways were investigated by Western blot analysis, immunocytochemistry and reporter assay. Additionally, the effect of CX-4945 on TGF-β1-induced migration and invasion was investigated by wound healing assay, Boyden chamber assay, gelatin zymography, and the quantitative real-time PCR. CX-4945 inhibits the TGF-β1-induced cadherin switch and the activation of key signaling molecules involved in Smad (Smad2/3, Twist and Snail), non-Smad (Akt and Erk), Wnt (β-catenin) and focal adhesion signaling pathways (FAK, Src and paxillin) that cooperatively regulate the overall process of EMT. As a result, CX-4945 inhibits the migration and invasion of A549 cells accompanied with the downregulation of MMP-2 and 9. Clinical evaluation of CX-4945 in humans as a single agent in solid tumors and multiple myeloma has established its promising pharmacokinetic, pharmacodynamic, and safety profiles. Beyond regression of tumor mass, CX-4945 may be advanced as a new therapy for cancer metastasis and EMT-related disorders.
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作者：
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影响因子：
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