Diosmin通过靶向FAK抑制NSCLC进展来降低蜗牛和细胞周期蛋白D1的稳定性
Diosmin reduces the stability of Snail and Cyclin D1 by targeting FAK to inhibit NSCLC progression
影响因子:8.30000
分区:医学1区 Top / 药物化学1区 全科医学与补充医学1区 药学1区 植物科学1区
发表日期:2024 Dec
作者:
Chenkang Ma, Mengxia Dan, Ying Wang, Chenying Shu, Min Jiao, Yuna Shao, Huiling Zhang, Chang Li, Yuanyuan Zeng, Jianjie Zhu, Jian-An Huang, Jianjun Li, Zeyi Liu
摘要
在不同的肿瘤中，非受体酪氨酸激酶局灶性粘附激酶（FAK）被上调，因此代表了癌症治疗的有希望的靶标。但是，FAK激酶抑制剂的发展面临许多挑战。因此，必须及时鉴定出新的，有效的FAK激酶抑制剂。通过分子对接鉴定靶FAK的小分子，并通过表面等离子体的共振（SPR）和细胞热移分析验证。我们使用CCK-8，菌落形成，EDU和Transwell分析和细胞周期分析研究了FAK激酶抑制剂的药理作用。通过诸如共免疫沉淀，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Diosmin（Dio）是FAK的抑制剂，并证明了其抗增殖性和抗抗激素效应在肺腺癌中。从机械上讲，DIO通过阻碍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来诱导细胞周期蛋白D1降解，同时抑制肿瘤增殖并通过降低蜗牛的mRNA稳定性，从而抑制癌症的癌症转移，从而抑制上皮间质转变（EMT）过程。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通过稳定细胞周期蛋白D1和Snail和Snail的肺腺癌中肿瘤促进作用，并建议DIO是FAK抑制的有前途的候选者。
Abstract
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.