CK2 inhibitor CX-4945 blocks TGF-β1-induced epithelial-to-mesenchymal transition in A549 human lung adenocarcinoma cells

• Published in: PloS one 2013-09, Vol.8 (9), p.e74342-e74342
• Main Authors: Kim, Jiyeon, Hwan Kim, Seong
• Format: Article
• Language: English
• Subjects: Activation; Adenocarcinoma; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Adhesion; AKT protein; Assaying; Boyden chamber; Cadherins; Cadherins - metabolism; Cancer; Casein; Casein kinase II; Casein Kinase II - antagonists & inhibitors; Cell adhesion & migration; Cell cycle; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Epidermal growth factor; Epithelial-Mesenchymal Transition - drug effects; Extracellular signal-regulated kinase; Focal adhesion kinase; Focal Adhesion Kinase 1 - metabolism; Gelatin; Gelatinase A; Gene expression; Genotype & phenotype; Humans; Immunocytochemistry; Inhibitors; Kinases; Laboratories; Lung cancer; Lung Neoplasms - pathology; Lungs; Mesenchyme; Metastases; Metastasis; Multiple myeloma; Naphthyridines - pharmacology; Neoplasm Invasiveness; Paxillin; Paxillin - metabolism; Pharmacodynamics; Pharmacology; Protein kinase C; Protein Kinase Inhibitors - pharmacology; R&D; Regression analysis; Research & development; Signal transduction; Signal Transduction - drug effects; Signaling; Smad protein; Smad Proteins - metabolism; Smad2 protein; Solid tumors; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1; Tumors; Wnt protein; Wnt Proteins - metabolism; Wound healing; β-Catenin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0074342

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.