Metformin Reverses Radiotherapy-Induced Pancreatic Cancer Cell Senescence by Alleviating the Unfolded Protein Response

Objective: Radiation therapy (RT) is the primary neoadjuvant modality for pancreatic ductal adenocarcinoma (PDAC), especially in borderline resectable or unresectable presentations. Despite its central role, the therapeutic efficacy of RT is markedly hindered by inherent resistance mechanisms in pancreatic cancer cells, the specific determinants of which are not yet fully understood. This study aims to elucidate the potential of metformin in enhancing the synergistic effects of RT against PDAC.. Methods: : Radiation therapy was confirmed to induce senescence in pancreatic cancer cell lines (PANC-1 and PANC-02) via immunofluorescence, SA-β-Gal staining, and immunoblot analysis. We assessed the resistance of senescent cancer cells to RT and examined the capacity of metformin to potentially reverse this resistance, employing SA-β-Gal staining, immunofluorescence, western blotting, and CCK8 assays. Results: : RT increased the expression of senescence biomarkers (p21, p16, and SA-β-Gal activity) in residual cancer cells. Senescent cancer cells exhibited resistance to RT both in vitro and in vivo. Furthermore, metformin effectively reversed this RT-induced resistance in senescent cancer cells in both experimental settings. Mechanistically, we observed a reduction in the unfolded protein response in senescent pancreatic cancer cells treated with RT and metformin. Conclusion: This study demonstrates that combining RT with metformin represents a potent strategy to eliminate senescent pancreatic cancer cells, suggesting its potential as a novel neoadjuvant therapeutic approach for refractory tumors in clinical practice.