[Study on anti-gastric cancer mechanism of Actinidia eriantha polysaccharides via regulation of energy metabolism reprogramming].

This study aims to investigate the anti-gastric cancer effects and mechanisms of Actinidia eriantha polysaccharides(AEPS) through the regulation of energy metabolism. In the animal experiment, 615 mice were used to establish a subcutaneous gastric cancer xenograft model, and the modeled mice were allocated into a model group and low-(50 mg·kg~(-1)·d~(-1)) and high-dose(100 mg·kg~(-1)·d~(-1)) AEPS groups. AEPS was administered via intraperitoneal injection for 14 days, and the tumor volume was measured via a caliper. Targeted energy metabolomics analysis was conducted on the tumor tissue. In the cell experiment, human gastric cancer HGC-27 cells were allocated into a control group and low-, medium-, and high-dose AEPS-containing serum groups. The CCK-8, wound healing, and Transwell assays were employed to assess the cell viability, migration, and invasion, respectively. The adenosine triphosphate(ATP) content, reactive oxygen species(ROS) level, activities of pyruvate dehydrogenase(PDH) and alpha-ketoglutarate dehydrogenase(α-KGDH), and nicotinamide adenine dinucleotide(NADH) level were measured via corresponding kits. The protein level of hypoxia-inducible factor-1alpha(HIF-1α) was determined by Western blot. The results showed that compared with that in the model group, the tumor volume in the AEPS high-dose group was significantly reduced. Metabolomics analysis revealed significant differences in 17 metabolites between the AEPS and model groups. KEGG pathway enrichment indicated involvement of the tricarboxylic acid(TCA) cycle, arginine metabolism, and glucose metabolism. Notably, key TCA intermediates including citrate, isocitrate, malate, and α-ketoglutarate presented reduced levels in the AEPS group compared with the model group. The cell experiment showed that compared with the control group, AEPS-containing serum treatment reduced gastric cancer cell viability, especially in the medium-and high-dose groups(P<0.05, P<0.01), and inhibited cell migration and invasion(P<0.05, P<0.01, P<0.001). The AEPS-containing serum treatment decreased the ATP content, ROS levels, PDH and α-KGDH activities, and NADH levels, particularly in the high-dose group(P<0.01). The protein level of HIF-1α was upregulated in the high-dose AEPS group(P<0.05). These results indicate that AEPS inhibits the TCA cycle by downregulating the expression of PDH, α-KGDH, and NADH and reducing the levels of citrate, isocitrate, malate, and α-ketoglutarate, thereby disrupting energy metabolism reprogramming, lowering ATP and ROS production, and ultimately suppressing the viability, invasion, and migration of gastric cancer cells. The underlying molecular mechanism may be associated with regulation of HIF-1α expression.