Diosmin reduces the stability of Snail and Cyclin D1 by targeting FAK to inhibit NSCLC progression

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Cyclin D1; Diosmin; FAK; Snail; Ubiquitin; mRNA stability.