Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling
Abstract Small cell lung cancer (SCLC) is a therapeutically challenging disease. Metformin, an effective agent for the treatment of type 2 diabetes, has been shown to have antitumour effects on many cancers, including non-small cell lung cancer (NSCLC) and breast cancer. Currently, the antitumour ef...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-87537-z |
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| author | Hong Xia Xue-jiao Tai Wang Cheng Yi Wu Dan He Li-feng Wang Hao Liu Shen-yi Zhang Yu-ting Sun Hang-zhi Liu Dan-dan Liu Hu-zi Zhao Fu-yun Ji Xi-hua Li |
| author_facet | Hong Xia Xue-jiao Tai Wang Cheng Yi Wu Dan He Li-feng Wang Hao Liu Shen-yi Zhang Yu-ting Sun Hang-zhi Liu Dan-dan Liu Hu-zi Zhao Fu-yun Ji Xi-hua Li |
| author_sort | Hong Xia |
| collection | DOAJ |
| description | Abstract Small cell lung cancer (SCLC) is a therapeutically challenging disease. Metformin, an effective agent for the treatment of type 2 diabetes, has been shown to have antitumour effects on many cancers, including non-small cell lung cancer (NSCLC) and breast cancer. Currently, the antitumour effects of metformin on SCLC and the underlying molecular mechanisms remain unclear. CCK-8, EdU, colony formation, flow cytometry, immunofluorescence, molecular docking, western blotting, nude mouse transplanted tumour model, and immunohistochemistry experiments were conducted to analyse gene functions and the underlying mechanism involved. In vitro experiments demonstrated that metformin inhibited the growth of SCLC cells (H446, H526, H446/DDP and H526/DDP), which was confirmed in xenograft mouse models in vivo. Additionally, metformin induced cell cycle arrest, apoptosis, and autophagy in these SCLC cells. The molecular docking results indicated that metformin has a certain binding affinity for EGFR. The western blotting results revealed that metformin decreased the expression of EGFR, p-EGFR, AKT, and p-AKT, which could be reversed by EGF and SC79. Moreover, metformin activated AMPK and inactivated mTOR, and compound C and SC79 increased the levels of p-mTOR. Metformin can not only enhance the antitumour effect of cisplatin but also alleviate the toxic effects of cisplatin on the organs of xenograft model animals. In summary, the current study revealed that metformin inhibits the growth of SCLC by inducing autophagy and apoptosis via suppression of the EGFR/AKT/AMPK/mTOR pathway. Metformin might be a promising candidate drug for combination therapy of SCLC. |
| format | Article |
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| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-a52840af3bd241e78811adebdf842f6a2025-08-20T02:14:59ZengNature PortfolioScientific Reports2045-23222025-02-0115111510.1038/s41598-025-87537-zMetformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signallingHong Xia0Xue-jiao Tai1Wang Cheng2Yi Wu3Dan He4Li-feng Wang5Hao Liu6Shen-yi Zhang7Yu-ting Sun8Hang-zhi Liu9Dan-dan Liu10Hu-zi Zhao11Fu-yun Ji12Xi-hua Li13Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineDepartment of Oncology, Taihe Hospital, Hubei University of MedicineSchool of Biomedical Engineering, Hubei University of MedicineSchool of Biomedical Engineering, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Science, Hubei University of MedicineAbstract Small cell lung cancer (SCLC) is a therapeutically challenging disease. Metformin, an effective agent for the treatment of type 2 diabetes, has been shown to have antitumour effects on many cancers, including non-small cell lung cancer (NSCLC) and breast cancer. Currently, the antitumour effects of metformin on SCLC and the underlying molecular mechanisms remain unclear. CCK-8, EdU, colony formation, flow cytometry, immunofluorescence, molecular docking, western blotting, nude mouse transplanted tumour model, and immunohistochemistry experiments were conducted to analyse gene functions and the underlying mechanism involved. In vitro experiments demonstrated that metformin inhibited the growth of SCLC cells (H446, H526, H446/DDP and H526/DDP), which was confirmed in xenograft mouse models in vivo. Additionally, metformin induced cell cycle arrest, apoptosis, and autophagy in these SCLC cells. The molecular docking results indicated that metformin has a certain binding affinity for EGFR. The western blotting results revealed that metformin decreased the expression of EGFR, p-EGFR, AKT, and p-AKT, which could be reversed by EGF and SC79. Moreover, metformin activated AMPK and inactivated mTOR, and compound C and SC79 increased the levels of p-mTOR. Metformin can not only enhance the antitumour effect of cisplatin but also alleviate the toxic effects of cisplatin on the organs of xenograft model animals. In summary, the current study revealed that metformin inhibits the growth of SCLC by inducing autophagy and apoptosis via suppression of the EGFR/AKT/AMPK/mTOR pathway. Metformin might be a promising candidate drug for combination therapy of SCLC.https://doi.org/10.1038/s41598-025-87537-zSCLCMetforminApoptosisAutophagyCell cycle arrest |
| spellingShingle | Hong Xia Xue-jiao Tai Wang Cheng Yi Wu Dan He Li-feng Wang Hao Liu Shen-yi Zhang Yu-ting Sun Hang-zhi Liu Dan-dan Liu Hu-zi Zhao Fu-yun Ji Xi-hua Li Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling Scientific Reports SCLC Metformin Apoptosis Autophagy Cell cycle arrest |
| title | Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling |
| title_full | Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling |
| title_fullStr | Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling |
| title_full_unstemmed | Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling |
| title_short | Metformin inhibits the growth of SCLC cells by inducing autophagy and apoptosis via the suppression of EGFR and AKT signalling |
| title_sort | metformin inhibits the growth of sclc cells by inducing autophagy and apoptosis via the suppression of egfr and akt signalling |
| topic | SCLC Metformin Apoptosis Autophagy Cell cycle arrest |
| url | https://doi.org/10.1038/s41598-025-87537-z |
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