Laboratory of Translational Therapeutics, Pharmacology Research Center, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Republic of Korea.
PLoS One. 2013 Sep 4;8(9):e74342. doi: 10.1371/journal.pone.0074342. eCollection 2013.
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.
上皮-间充质转化（EMT）是癌症转移和侵袭的主要表型。作为一种可成药的癌症靶点，蛋白激酶 CK2（正式命名为酪蛋白激酶 2）的抑制作用已被认为是治疗 EMT 控制的癌症转移的一种很有前途的治疗策略。本研究旨在评估 CK2 抑制剂 CX-4945 对 TGF-β1 诱导的 A549 人肺腺癌细胞 EMT 过程中癌细胞迁移和侵袭的影响。
用 TGF-β1（5ng/ml）和 CX-4945 处理 A549 细胞，评估 CX-4945 对 TGF-β1 诱导的 EMT 的影响。通过 Western blot 分析、免疫细胞化学和报告基因检测，研究 CX-4945 对 TGF-β1 诱导的钙粘蛋白转换和参与 Smad、非 Smad、Wnt 和黏着斑信号通路的关键信号分子的激活的影响。此外，通过划痕愈合试验、Boyden 室试验、明胶酶谱分析和定量实时 PCR，研究 CX-4945 对 TGF-β1 诱导的迁移和侵袭的影响。
CX-4945 抑制 TGF-β1 诱导的钙粘蛋白转换和参与 Smad（Smad2/3、Twist 和 Snail）、非 Smad（Akt 和 Erk）、Wnt（β-catenin）和黏着斑信号通路（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 的全过程。结果，CX-4945 抑制 A549 细胞的迁移和侵袭，并伴有 MMP-2 和 9 的下调。
CX-4945 在人类实体瘤和多发性骨髓瘤中的临床评估已经确立了其有前途的药代动力学、药效学和安全性特征。除了肿瘤体积的消退外，CX-4945 可能被推进作为癌症转移和 EMT 相关疾病的新疗法。
