The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer

Abstract Background: Diabetes is significantly associated with increased cancer risk, with several studies reporting hyperglycemia as a primary oncogenic stimulant. Glucose metabolism is linked to numerous metabolic pathways, making it difficult to specify the mechanisms underlying hyperglycemia-induced cancer progression. Here, we focused on the polyol pathway, which is dramatically activated under hyperglycemia and causes diabetic complications. We tested the possibility that polyol pathway-derived fructose facilitates hyperglycemia-induced gastric cancer metastasis. Methods : We performed bioinformatics analysis of gastric cancer datasets and immunohistochemical analyses of gastric cancer specimens, followed by transcriptomic and proteomic analyses to evaluate phenotypic changes in gastric cancer cells. We used two xenograft models to evaluate gastric cancer metastasis in patients with diabetes. Results : We observed a clinical association between the polyol pathway and gastric cancer progression. In gastric cancer cell lines, hyperglycemia enhanced cell migration and invasion, cytoskeletal rearrangement, and epithelial-mesenchymal transition (EMT). The hyperglycemia-induced acquisition of metastatic potential was mediated by increased fructose derived from the polyol pathway, which stimulated the nuclear ketohexokinase-A (KHK-A) signaling pathway, thereby inducing EMT by repressing the CDH1 gene. In two different xenograft models of cancer metastasis, gastric cancers overexpressing AKR1B1, which catalyzes the rate-limiting step in the polyol pathway, were found to be highly metastatic in diabetic mice. Conclusions : Hyperglycemia induces fructose formation through the polyol pathway, which in turn stimulates the KHK-A signaling pathway, driving gastric cancer metastasis by inducing EMT. Thus, the polyol and KHK-A signaling pathways could be potential therapeutic targets for lowering the metastatic risk in gastric cancer patients with diabetes.