Abstract
BackgroundThe 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.Materials and MethodsThe 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.ResultsCX-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.ConclusionsClinical 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.
Highlights
The epithelial-to-mesenchymal transition (EMT) is a major phenotype of cancer metastasis and invasion that occurs in epithelial tumors and accounts for 90% of human tumors [1,2,3,4]
The inhibitory effect of CX-4945 on Tumor growth factor (TGF)-β1-induced EMT was confirmed by visualizing the expression of markers (Figure 1D); consistent with Figure 1C, CX-4945 inhibited the decrease of E-cadherin and increase of vimentin that were induced by TGF-β1
The phosphorylation and expression of paxillin was not induced by TGF-β1, but those were strongly inhibited by CX-4945. These results suggest that the expression and/or activation of focal adhesion kinase (FAK), Src, and paxillin are involved in the inhibitory effect of CX-4945 on the TGF-β1induced invasion of A549 cells, and suggest that its inhibitory effect of TGF-β1-induced EMT could be not cell linedependent
Summary
The epithelial-to-mesenchymal transition (EMT) is a major phenotype of cancer metastasis and invasion that occurs in epithelial tumors and accounts for 90% of human tumors [1,2,3,4]. Trimers consisting of phosphorylated Smad2/3 and Smad translocate to the nucleus, where they cooperate with transcription factors such as Snail and Twist to repress the expression of epithelial markers and activate the expression of mesenchymal markers at the mRNA level [10,11,12]. This signaling is referred to as TGF-β-activated Smad signaling in EMT. 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. 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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