Metastasis is the main cause of mortality in patients with cancer. Epithelial–mesenchymal transition (EMT), a crucial process in cancer metastasis, is an established target for antimetastatic drug development. LFG-500, a novel synthetic flavonoid, has been revealed as a potential antitumor agent owing to its various activities, including modulation of EMT in the inflammatory microenvironment. Here, using a transforming growth factor beta (TGF-β)-induced EMT models, we found that LFG-500 inhibited EMT-associated migration and invasion in human breast cancer, MCF-7, and lung adenocarcinoma, A549, cell lines, consistent with the observed downregulation of YAP activity. Further studies demonstrated that LGF-500-induced suppression of YAP activation was mediated by integrin-linked kinase (ILK), suggesting that the ILK/YAP axis might be feasible target for anti-EMT and antimetastatic treatments, which was verified by a correlation analysis with clinical data and tumor specimens. Hence, our data support the use of LGF-500 as an antimetastatic drug in cancer therapy and provide evidence that the ILK/YAP axis is a feasible biomarker of cancer progression and a promising target for repression of EMT and metastasis in cancer therapy.
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The authors are grateful to Professor Qing-long Guo, who kindly provided LFG-500, to Professor Xiu-ping Zhou for YAP (S127A) plasmid, and to Dr. Hai-ying Li and Dr. Ying Zhang (Department of pathology, Basic Medical Sciences of Xuzhou Medical University) for the assessment of immunohistochemistry. This work was supported by the National Natural Science Foundation of China (grant no. 81402969 and 81973341), supported by the 333 High-level Talents Project of Jiangsu Province, the Six Talent Peaks Project in Jiangsu Province (grant no. 2017-SWYY-075), the Science and Technology Program of Guangzhou (grant no. 202002030010), and the Fundamental Research Funds for the Central Universities (grant no. 21620426), the Science and Technology Innovation Promoting Project of Xuzhou (grant no. KC20066), and the National Demonstration Center for Experimental Basic Medical Science Education (Xuzhou Medical University).
The authors declare no competing interests.
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Li, Cl., Li, J., Gong, Sy. et al. Targeting the ILK/YAP axis by LFG-500 blocks epithelial–mesenchymal transition and metastasis. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00655-y
- epithelial–mesenchymal transition