Sci Rep. 2025 Mar 22. 15(1): 9941
Glycolysis is a critical metabolic pathway in cancer cells, fulfilling their energy requirements, supporting biosynthesis, maintaining redox balance, and enabling survival in hostile environments. Alpha-enolase (ENO1) has been identified as a key promoter of tumor progression through its involvement in glycolysis. This study aims to elucidate the relationship between ENO1, glycolysis, and gemcitabine sensitivity in pancreatic cancer (PC). The expression levels of ENO1 in PC were analyzed using the GEPIA2 database, Kaplan-Meier survival plots, and immunohistochemistry (IHC). To assess the impact of ENO1 on gemcitabine sensitivity, we manipulated ENO1 expression in PC cell lines through overexpression and silencing techniques. Subsequent analyses included flow cytometry assays, glucose uptake and lactate production measurements, and cytotoxicity assays. The underlying mechanisms by which ENO1 modulates gemcitabine sensitivity were explored using Western blotting (WB). ENO1 was found to be significantly overexpressed in PC tissues, and elevated ENO1 levels were associated with poorer prognosis in PC patients. Overexpression of ENO1 reduced the sensitivity of PC cells to gemcitabine, enhancing cell proliferation, migration, and invasion by altering the cell cycle and inhibiting apoptosis. Conversely, silencing ENO1 decreased glycolysis in PC cells and heightened their sensitivity to gemcitabine. Furthermore, glycolysis inhibition-achieved through ENO1 knockdown, glucose deprivation, or treatment with 2-Deoxy-D-glucose (2-DG)-further enhanced the susceptibility of PC cells to gemcitabine. Mechanistically, ENO1 was found to regulate the expression of gemcitabine resistance-related genes, particularly ribonucleotide reductase catalytic subunit M1 (RRM1), via MYC through the glycolytic pathway, thereby contributing to gemcitabine resistance. This study demonstrates that ENO1 plays a crucial role in PC progression and is closely linked to gemcitabine resistance through its regulation of the glycolytic pathway.
Keywords: ENO1; Gemcitabine sensitivity; Glycolysis; PC; RRM1