Mechanistic study of metformin-mediated modulation of cellular senescence and radiosensitivity in pancreatic cancer
10.19405/j.cnki.issn1000-1492.2025.07.017
- Author:
Wenjin Xu
1
;
Yuxin Xie
1
;
Xinyue Lin
1
;
Xin Wang
1
;
Wei Jiang
1
;
Shijie Wei
2
;
Qiang Liu
3
;
Xiang Liao
3
Author Information
1. Dept of Medical Imaging，The Affiliated Hospital of Jiangsu University，Zhenjiang 212001
2. Dept of Medical Imaging，The Affiliated Jiangyin Hospital of Nantong University，Jiangyin 214400
3. Dept of Medical Laboratory，The Affiliated Hospital of Jiangsu University，Zhenjiang 212001
- Publication Type:Journal Article
- Keywords:
metformin;
pancreatic carcinoma;
radioresistance;
cellular senescence;
PERK inhibitor;
PERK/P-eIF2/ATF4 signaling pathway
- From:
Acta Universitatis Medicinalis Anhui
2025;60(7):1282-1290
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To study the effect of metformin sensitizing pancreatic cancer cells with radiotherapy, with a focus on elucidating the underlying mechanisms of radiotherapy resistance. In particular, the role of the PERK/P-eIF2/ATF4 signaling pathway in mediating these effects was preliminarily explored.
Methods :Pancreatic cancer cell lines(PANC-1 and PANC-2) were categorized into control, radiotherapy, and drug treatment groups. Following the respective treatments, cell proliferation inhibition was assessed using the CCK-8 assay, colony formation assays, and cell death staining. Senescence was quantified by β-galactosidase(SA-β-Gal) staining. The expression of cell cycle regulators(P21, P16, γ-H2AX), apoptosis markers(Bax, Bcl-2, Cleaved caspase-3), and pathway-related proteins(PERK, P-eIF2, ATF4) was evaluated by Western blot and immunofluorescence. To further investigate the role of the PERK/P-eIF2/ATF4 axis in metformin-mediated modulation of pancreatic cancer cell senescence and radiosensitization, selective inhibitors(GSK2606414) and agonists(MK-28) of PERK were employed.
Results :Radiotherapy markedly upregulated senescence-associated markers(P21, P16, γ-H2AX, and β-galactosidase activity) in pancreatic cancer cells. Senescent cells exhibited enhanced proliferative activity and increased tumor volume both in vitro and in vivo. Metformin mitigated radiotherapy-induced senescence by reducing the expression of senescence markers and significantly suppressing the clonogenic and proliferative capacity of treated cells. Mechanistically, radiotherapy activated the PERK signaling pathway, leading to increased expression of PERK, P-eIF2, and ATF4, thereby driving cellular senescence. Pharmacological inhibition of PERK reduced β-galactosidase activity, while PERK activation further promoted the expression of senescence-associated proteins—an effect that was reversed by metformin.
Conclusion:Metformin inhibits the activation of the PERK/P-eIF2/ATF4 signaling pathway in pancreatic cancer cells following radiotherapy, thereby delaying cellular senescence and reducing the associated radiotherapy resistance of senescent cells. This modulation contributes to the sensitization of pancreatic cancer cells to radiotherapy.
- Full text:2026030516150367139二甲双胍缓解胰腺癌细胞衰老并增敏放疗的效果及机制_许文金.pdf
