Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, 221004, China.
MOE Key Laboratory of Tumor Molecular Biology, Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.
Acta Pharmacol Sin. 2021 Nov;42(11):1847-1859. doi: 10.1038/s41401-021-00655-y. Epub 2021 Apr 20.
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.
转移是癌症患者死亡的主要原因。上皮-间充质转化（EMT）是癌症转移的关键过程，已成为抗转移药物开发的既定靶点。LFG-500 是一种新型合成类黄酮，由于其多种活性，包括在炎症微环境中调节 EMT，已被证明是一种潜在的抗肿瘤剂。在这里，我们使用转化生长因子-β（TGF-β）诱导的 EMT 模型，发现 LFG-500 抑制了人乳腺癌 MCF-7 和肺腺癌细胞系 A549 的 EMT 相关迁移和侵袭，这与观察到的 YAP 活性下调一致。进一步的研究表明，LFG-500 诱导的 YAP 激活抑制是由整合素连接激酶（ILK）介导的，表明 ILK/YAP 轴可能是抗 EMT 和抗转移治疗的可行靶点，这通过与临床数据和肿瘤标本的相关性分析得到了验证。因此，我们的数据支持将 LFG-500 用作癌症治疗中的抗转移药物，并提供证据表明，ILK/YAP 轴是癌症进展的可行生物标志物，也是抑制 EMT 和转移的有前途的癌症治疗靶点。
