Ellagic acid is associated with reduced pancreatic carcinogenesis and modulation of the IL-6/STAT3 pathway

The 5-year survival of pancreatic ductal adenocarcinoma (PDAC) remains about 10% despite therapeutic advances, underscoring the need for effective preventive and early intervention strategies. Ellagic acid (EA), a naturally occurring polyphenol, has been associated with demonstrated antitumor activity in several malignancies. However, its potential role in preventing PDAC development remains unclear. In this study, we examined the chemopreventive potential and underlying mechanisms of EA in a hamster model of PDAC induced by a high-fat diet and N-nitrosobis(2-oxopropyl)amine. Dietary EA (0.1% w/w) was associated with significantly reduction in both the incidence and multiplicity of PDACs compared to controls. The proportion of histologically normal pancreatic ducts increased and the Ki-67 labeling index decreased in pancreatic intraepithelial neoplasia (PanIN) following EA exposure. In vitro, cell proliferation decreased in a dose-dependent manner, G1 arrest was induced, and invasion was diminished after EA treatment. Multiplex Western blotting revealed lower inhibition of the IL-6/STAT3 pathway. The proportion of pSTAT3-positive cells in hamster PanINs and PDACs was significantly lower in the EA-treated groups than in controls. Because a high-fat diet is known to elevate adipocytokines, and resistin (Res) has been implicated in STAT3 regulation, the Res/STAT3 axis was also examined. Res-associated promotion of invasion was observed but there was no proliferation in vitro, and pSTAT3 expression did not increase. Similarly, serum Res levels did not differ significantly across groups, suggesting a limited contribution of the Res/STAT3 pathway in this hamster model. EA treatment was associated with reduced pancreatic carcinogenesis in vivo. The IL-6/STAT3 pathway appears to be a primary molecular target under our experimental conditions, whereas the contribution of Res is likely minimal. These findings support the potential of EA as a preventive agent against pancreatic cancer.