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Volume 18, Issue 4
  • ISSN: 1874-4710
  • E-ISSN: 1874-4729

Abstract

Introduction

Metformin induces radiation sensitivity in cancer cells, including colorectal cancer cells; however, the exact molecular mechanisms underlying its radiosensitive effects are not yet known. In this study, we investigated the role of the p53/miR-34a/SIRT1 pathway in the radiosensitivity of colon cancer cells.

Methods

The study was carried out from 2020 to 2022 at the Qazvin University of Medical Science's Cellular and Molecular Research Center. Two colorectal cancer cell lines (SW480 and SW620) obtained from primary and secondary tumors derived from a single patient were used as the study samples. After subjecting the cells to 50 Gy of radiation, we generated radioresistant cell lines. Resistant cells were treated with 50 µM metformin. Metformin-treated and untreated resistant cells constituted the study groups. The expression levels of miR-34-a and Sirtunin1 (SIRT1) were evaluated using Quantitative Real-time PCR. The rates of cell proliferation and apoptosis were assessed using a Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Western blot analysis was performed to quantify the expression of proteins. For statistical analysis, the Student's t-test was carried out to examine the mean differences between the two groups, and analysis of variance (ANOVA) was used to examine additional groups.

Results

Our results showed that the expression of miR-34-a was downregulated (0.29 ± 0.11) in radiation-resistant cancer cells ( <0.001), while the expression of SIRT-1 was upregulated (4.5 ± 0.25) ( <0.001). Metformin increased the radiosensitivity of colon cancer cells in a time- and dose-dependent manner. Treatment with 50 µM metformin after 48h caused decreased cell viability and increased apoptosis in resistant cells. We observed downregulation of SIRT-1 (1.1 ± 0.45) and upregulation of miR-34-a (4.3 ± 1.3) ( <0.001) in metformin-treated cells. In contrast, western blotting results showed the upregulation of acetylated P53 in metformin-treated cells. Metformin function was reversed by SIRT1 inhibitors or by transfection with miR-34-a overexpressing plasmids.

Conclusion

Based on these results, one of the radiosensitivity mechanisms of metformin in colorectal cancer is the modulation of the p53/miR-34a/SIRT1 loop.

© 2025 Bentham Science Publishers
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2025-02-04
2025-06-20

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/content/journals/crp/10.2174/0118744710331660250127115004
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Role of the p53/miR-34a/SIRT1 Feedback Loop in Metformin-induced Radiosensitivity of Colorectal Cancer Cells
Current Radiopharmaceuticals 18, 340 (2025); https://doi.org/10.2174/0118744710331660250127115004
/content/journals/crp/10.2174/0118744710331660250127115004
/content/journals/crp/10.2174/0118744710331660250127115004
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  • Article Type:     Research Article
Keyword(s): apoptosis; cell proliferation; Colorectal cancer; metformin; microRNAs; p53 pathway; radiosensitization; sirtuin 1

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