7-Geranyloxycoumarin modulated metastatic potential of osteosarcoma cells via interaction with MMPs and JAK1/2.

Abstract

Osteosarcoma (OS) is a highly aggressive bone cancer that primarily affects young adults. The tumor microenvironment and molecular mediators, including Janus kinases (JAKs) and matrix metalloproteinases (MMPs), significantly influence OS metastasis; activation of the JAK/STAT pathway enhances MMP expression and activity, promoting OS metastasis. 7-Geranyloxycoumarin, a natural agent found in various edible fruits and vegetables, possesses valuable pharmaceutical activities. This study aimed to investigate the effects of 7-geranyloxycoumarin on the metastasis of OS cells for the first time. To achieve this, a protein-protein interaction (PPI) network was constructed from the potential molecular and pathogenic targets associated with 7-geranyloxycoumarin and OS to identify overlapping targets. Subsequently, GO and KEGG pathway enrichment analyses were conducted. Molecular docking and dynamic simulations were also performed to elucidate the binding affinity of 7-geranyloxycoumarin with JAK1 and JAK2. For in vitro studies, 7-geranyloxycoumarin was first extracted from Ferula szowitsiana using thin-layer chromatography. The cells were then treated and evaluated for viability, apoptosis, migration, invasion, adhesion, and MMPs activity. The study identified 50 shared targets and revealed MMP-2, MMP-9, JAK1, and JAK2 as hub genes, confirmed through enrichment analyses. Molecular docking revealed strong interactions between 7-geranyloxycoumarin and JAK1 and JAK2 proteins, and molecular dynamics simulations indicated both conformational flexibility and binding stability of the ligand-protein complex. Moreover, experimental studies demonstrated that 7-geranyloxycoumarin did not induce apoptosis but significantly altered the migration, invasion, and adhesion of OS cells by inhibiting the activity of MMPs. In conclusion, 7-geranyloxycoumarin is proposed as a promising therapeutic agent for targeting metastasis in OS cells.