Dihydroartemisinin suppresses metastatic potential and induces apoptosis in gastric adenocarcinoma: An integrative experimental and computational analysis revealing inhibition of MMP14 and promotion of oxidative stress.

PURPOSE: Gastric adenocarcinoma is a highly aggressive malignant tumor characterized by a complex tumor microenvironment and significant degradation of extracellular matrix. Studies highlighted the critical role of MMP14 in tumor metastasis and cell proliferation within gastric adenocarcinoma. Furthermore, dihydroartemisinin has demonstrated a significant ability to reduce tumor invasiveness and promote apoptosis. However, the specific mechanism of dihydroartemisinin in gastric adenocarcinoma treatment remains unclear. This study investigated key targets of dihydroartemisinin and its signaling pathway through inhibiting tumor metastasis and promoting apoptosis in gastric adenocarcinoma.

METHODS: The human gastric adenocarcinoma AGS cell was selected to establish cell experiments with CCK-8, V-FITC/PI and scratch assay in order to investigate effects of dihydroartemisinin on cell proliferation, apoptosis and migration. We screened differential gene targets by machine learning and bioinformatics analysis of GSE27342 and GeneCards database. RT-qPCR, survival analysis, pan-tumor analysis and immune infiltration analysis were also performed on the differential gene targets. The stability of dihydroartemisinin binding to key proteins was verified using computer simulations.

RESULTS: The results of cellular experiments showed that dihydroartemisinin at 10 μg/mL significantly inhibited proliferation and invasiveness and promoted apoptosis of AGS cells. Bioinformatics and machine learning analysis screened the key target MMP14. RT-qPCR revealed that dihydroartemisinin significantly inhibited the gene expression of MMP14. The results of molecular dynamics showed binding free energy of MMP14/Dihydroartemisinin was -30.61 ± 1.29 kcal/mol.

CONCLUSION: In this study, we found dihydroartemisinin not only reduced invasiveness of gastric adenocarcinoma cells by down-regulating MMP14 expression and interfering with degradation of extracellular matrix, but also promoted apoptosis by inducing activation of relevant apoptotic signaling pathways, thus effectively inhibiting the growth and progression of gastric adenocarcinoma.