ArticleExperimental & molecular medicine2024
The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer.
Article in Experimental & molecular medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.Nature aging · 2026Article
- Luteolin inhibits hyperglycemia-induced epithelial-mesenchymal transition and malignant progression in gastric cancer via targeting AKR1B1-mediated glucose metabolism.Clinical & experimental metastasis · 2026Article
- Review
- Deciphering programmed cell death for gastric cancer prognosis: AKR1B1 as a key player.Journal of applied genetics · 2026Article
- Fructose: metabolic signal and modern hazard.Nature metabolism · 2026Review
- Microglial fructose metabolism is essential for glioblastoma growth.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Exercise-Induced Irisin: A Novel Strategy for Neuroinflammation Alleviation and Neurorepair in Diabetic Retinopathy.International journal of molecular sciences · 2026Review
- Unraveling Diabetes Mellitus-Driven Tumorigenesis: From Pathophysiological Mechanisms, Therapeutic Drugs to Tailor-Made Nanosystems.International journal of nanomedicine · 2026Review
- Structure-Based Virtual Screening for KHK-A Inhibitors with Anti-Hepatocellular Carcinoma Activity.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Bioactive assessment of hexahydroquinoline derivatives preparedRSC medicinal chemistry · 2025Article
- Aldose Reductase Involvement in EMT: Emerging Insights and Current Proposed Molecular Mechanisms.Biology · 2025Review
- Fructose metabolism and its roles in metabolic diseases, inflammatory diseases, and cancer.Molecular biomedicine · 2025Review
- Association Between Gestational Diabetes Mellitus and Risk of Overall and Site-Specific Cancers (Pancreatic, Liver, Thyroid, Lung): A Systematic Review and Meta-Analysis.Life (Basel, Switzerland) · 2025Review
- Review
- Article
- Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.International journal of medical sciences · 2025Review
- Exploring fructose metabolism as a potential therapeutic approach for pancreatic cancer.Cell death and differentiation · 2024Article
- Regulation of Fructose Metabolism in Nonalcoholic Fatty Liver Disease.Biomolecules · 2024Review
- Metabolic Signaling in Cancer Metastasis.Cancer discovery · 2024Review
- Aldo-keto reductases: Role in cancer development and theranostics.Oncology research · 2024Review
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Authors and funding
6 authors at 2 institutions in 3 countries.
Funding
Abstract
Diabetes might be associated with increased cancer risk, with several studies reporting hyperglycemia as a primary oncogenic stimulant. Since glucose metabolism is linked to numerous metabolic pathways, it is 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 investigated whether polyol pathway-derived fructose facilitates hyperglycemia-induced gastric cancer metastasis. 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. Consequently, we found 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 were found to be highly metastatic in diabetic mice, but these effects of AKR1B1 were attenuated by KHK-A knockdown. In conclusion, 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 to decrease the metastatic risk in gastric cancer patients with diabetes.
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