Resveratrol Inhibits Pancreatic Cancer Progression by Regulating CDC42 Succinylation and Disrupting the Extracellular Matrix.

Abstract

Pancreatic cancer (PC) is a highly lethal malignancy with significant drug resistance and recurrence. This study explores the molecular mechanisms by which resveratrol (RES) inhibits PC proliferation, invasion, and migration, aiming to provide new insights for future therapeutic strategies. Network pharmacology was used to construct a component-pathway-target network diagram for the effect of RES on PC. Transwell assays were used to analyze cell invasion. In addition, scratch assays were conducted to evaluate cell migration ability, and qPCR was utilized to monitor the mRNA expression levels of genes. Immunofluorescence and Western blotting were applied to detect protein expression. The results demonstrate that RES exhibits a significant inhibitory effect on PC cells at different concentrations, with 50 μmol/L RES showing the most pronounced inhibition. This observation was further confirmed by Transwell and scratch assays, which showed that RES significantly inhibits PC cell proliferation, invasion, and migration. Network pharmacology analysis suggests that RES may act on the Rap1 pathway to suppress the progression of PC. In vitro experiments confirmed that RES downregulates the expression of CDC42, MMP2, and MMP9. Notably, immunoprecipitation experiments revealed that RES induces the succinylation of CDC42, which, in turn, inhibits the CDC42 signaling pathway. This disruption leads to the destabilization of the extracellular matrix (ECM), thereby impeding tumor progression. This study demonstrates that RES significantly inhibits the proliferation, invasion, and migration of PC cells by mediating the succinylation of CDC42, which in turn inhibits the CDC42 signaling pathway and disrupts the dynamics of the ECM. This mechanism highlights the potential of RES as an anticancer agent and provides new insights for the development of therapeutic strategies for PC.