Cardiotoxin III suppresses the invasiveness of MDA-MB-231 cells by targeting proto-oncogene tyrosine-protein kinase Src and reversing mesenchymal-to-epithelial transition |
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Authors: | Pei-Chien Tsai Yi-Ling Lin Yaw-Syan Fu Long-Sen Chang |
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Institution: | 1. Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan;2. Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan;3. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan |
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Abstract: | The epithelial-to-mesenchymal transition is the first step required for breast cancer to initiate metastasis. The aberrant activation of proto-oncogene tyrosine-protein kinase Src regulates multiple functions during tumor progression. Cardiotoxin III, a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity; however, the effect of cardiotoxin III on the epithelial-to-mesenchymal transition of cancer cells remains elusive. Exposure of MDA-MB-231 cells to cardiotoxin III resulted in morphological changes and upregulation of E-cadherin with a concomitant decrease in N-cadherin and vimentin protein levels, resulting in the inhibition of cell migration and invasion. Cardiotoxin III induced downregulation of snail and slug expression. Simultaneously, cardiotoxin III suppressed Src phosphorylation and downstream activation of focal adhesion kinase, of the docking protein p130cas, and of paxillin. In addition, cardiotoxin III inhibited the phosphorylation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. The Src specific inhibitor 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo3,4-d]pyrimidine decreased in the phosphorylation and the expression changes of epithelial-to-mesenchymal transition markers in a similar way. Thus, cardiotoxin III has a novel anticancer effect by suppressing proto-oncogene tyrosine-protein kinase activity, reversing epithelial-to-mesenchymal transition. |
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Keywords: | CTX III EMT MDA-MB-231 cells Src |
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