title: CK2 inhibitor CX-4945 blocks TGF-β1-induced epithelial-to-mesenchymal transition in A549 human lung adenocarcinoma cells.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Translational Therapeutics, Pharmacology Research Center, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.forename: Seong
authors.initials: S
authors.lastname: Hwan Kim
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D015820:Cadherins / Q000378:metabolism; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009287:Naphthyridines / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism; D010619:Phenazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; D009287:Naphthyridines; D051419:Paxillin; D010619:Phenazines; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; C555142:silmitasertib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D047390:Casein Kinase II
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