Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou 215006, China; Institute of Respiratory Diseases, Soochow University, Suzhou 215006, China.
Institute of Respiratory Diseases, Soochow University, Suzhou 215006, China.
Phytomedicine. 2024 Dec;135:156135. doi: 10.1016/j.phymed.2024.156135. Epub 2024 Oct 9.
In different tumours, focal adhesion kinase (FAK), a nonreceptor tyrosine kinase, is upregulated and hence, it represents a promising target for cancer therapy. However, the development of FAK kinase inhibitors has faced a number of challenges. It is therefore imperative that new, effective FAK kinase inhibitors be identified promptly.
Small molecules that target FAK were identified through molecular docking and validated through surface plasmon resonance (SPR) and cell thermal shift analysis. We investigated the pharmacological effects of FAK kinase inhibitors using CCK-8, colony formation, EdU, and Transwell assays and cell cycle analysis. The molecular mechanism was determined via methods such as coimmunoprecipitation, RNA pull-down and RNA immunoprecipitation.
Here, we confirmed that diosmin (Dio) is an inhibitor of FAK and demonstrated its anti-proliferative and anti-metastatic effects in lung adenocarcinoma. Mechanistically, Dio inhibited tumour proliferation and metastasis by impeding the catalytic activity of FAK. Dio activated the ubiquitin proteasome pathway to induce Cyclin D1 degradation, while inhibiting tumour proliferation and reversing the epithelial mesenchymal transition (EMT) process by reducing the mRNA stability of Snail, thereby inhibiting cancer metastasis. In addition, the inhibitory effect of Dio on lung adenocarcinoma was validated in a mouse xenograft model.
These results support the tumour-promoting role of FAK in lung adenocarcinoma by stabilizing Cyclin D1 and Snail and suggest that Dio is a promising candidate for FAK inhibition.
在不同的肿瘤中，黏着斑激酶（FAK）作为一种非受体酪氨酸激酶被上调，因此它是癌症治疗的一个有前途的靶点。然而，FAK 激酶抑制剂的开发面临着许多挑战。因此，迫切需要尽快发现新的、有效的 FAK 激酶抑制剂。
通过分子对接鉴定靶向 FAK 的小分子，并通过表面等离子体共振（SPR）和细胞热转移分析进行验证。我们通过 CCK-8、集落形成、EdU 和 Transwell 检测和细胞周期分析来研究 FAK 激酶抑制剂的药理作用。通过免疫共沉淀、RNA 下拉和 RNA 免疫沉淀等方法确定分子机制。
在这里，我们证实了橙皮苷（Dio）是 FAK 的抑制剂，并证明了它在肺腺癌中的抗增殖和抗转移作用。机制上，Dio 通过抑制 FAK 的催化活性来抑制肿瘤的增殖和转移。Dio 激活了泛素蛋白酶体途径，诱导 Cyclin D1 降解，同时通过减少 Snail 的 mRNA 稳定性来抑制肿瘤增殖和逆转上皮间质转化（EMT）过程，从而抑制癌症转移。此外，在小鼠异种移植模型中验证了 Dio 对肺腺癌的抑制作用。
这些结果支持 FAK 在肺腺癌中通过稳定 Cyclin D1 和 Snail 促进肿瘤的作用，并表明 Dio 是 FAK 抑制的一个有前途的候选药物。
