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image of Role of the p53/miR-34a/SIRT1 Feedback Loop in Metformin-induced Radiosensitivity of Colorectal Cancer Cells

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.

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2025-02-04
2025-03-30

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References

  1. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J. Clin. 2021 71 3 209 249 10.3322/caac.21660 33538338
    [Google Scholar]
  2. Jeong Y.K. Kim M.S. Lee J.Y. Kim E.H. Ha H. Metformin radiosensitizes p53-deficient colorectal cancer cells through induction of G2/m arrest and inhibition of DNA repair proteins. PLoS One 2015 10 11 e0143596 10.1371/journal.pone.0143596 26599019
    [Google Scholar]
  3. Clifford R.E. Gerrard A.D. Fok M. Vimalachandran D. Metformin as a radiosensitiser for pelvic malignancy: A systematic review of the literature. Eur. J. Surg. Oncol. 2021 47 6 1252 1257 10.1016/j.ejso.2020.12.009 33358075
    [Google Scholar]
  4. Hua Y. Zheng Y. Yao Y. Jia R. Ge S. Zhuang A. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J. Transl. Med. 2023 21 1 403 10.1186/s12967‑023‑04263‑8 37344841
    [Google Scholar]
  5. Ng C.A.W. Jiang A.A. Toh E.M.S. Ng C.H. Ong Z.H. Peng S. Tham H.Y. Sundar R. Chong C.S. Khoo C.M. Metformin and colorectal cancer: A systematic review, meta-analysis and meta-regression. Int. J. Colorectal Dis. 2020 35 8 1501 1512 10.1007/s00384‑020‑03676‑x 32592092
    [Google Scholar]
  6. Chen L. Liao F. Jiang Z. Zhang C. Wang Z. Luo P. Jiang Q. Wu J. Wang Q. Luo M. Li X. Leng Y. Ma L. Shen G. Chen Z. Wang Y. Tan X. Gan Y. Liu D. Liu Y. Shi C. Metformin mitigates gastrointestinal radiotoxicity and radiosensitises P53 mutation colorectal tumours via optimising autophagy. Br. J. Pharmacol. 2020 177 17 3991 4006 10.1111/bph.15149 32472692
    [Google Scholar]
  7. de Mey S. Jiang H. Corbet C. Wang H. Dufait I. Law K. Bastien E. Verovski V. Gevaert T. Feron O. De Ridder M. Antidiabetic biguanides radiosensitize hypoxic colorectal cancer cells through a decrease in oxygen consumption. Front. Pharmacol. 2018 9 1073 10.3389/fphar.2018.01073 30337872
    [Google Scholar]
  8. Zannella V.E. Dal Pra A. Muaddi H. McKee T.D. Stapleton S. Sykes J. Glicksman R. Chaib S. Zamiara P. Milosevic M. Wouters B.G. Bristow R.G. Koritzinsky M. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin. Cancer Res. 2013 19 24 6741 6750 10.1158/1078‑0432.CCR‑13‑1787 24141625
    [Google Scholar]
  9. Muaddi H. Chowdhury S. Vellanki R. Zamiara P. Koritzinsky M. Contributions of AMPK and p53 dependent signaling to radiation response in the presence of metformin. Radiother. Oncol. 2013 108 3 446 450 10.1016/j.radonc.2013.06.014 23891087
    [Google Scholar]
  10. Saffari F. Momeni A. Ramezani M. Ansari Y. Moghbelinejad S. Metformin caused radiosensitivity of breast cancer cells through the expression modulation of miR-21-5p/SESN1axis. Asian Pac. J. Cancer Prev. 2023 24 11 3715 3727 10.31557/APJCP.2023.24.11.3715 38019229
    [Google Scholar]
  11. Mostaghimi T. Bahadoran E. Bakht M. Taheri S. Sadeghi H. Babaei A. Role of lncRNAs in Helicobacter pylori and Epstein-Barr virus associated gastric cancers. Life Sci. 2024 336 122316 10.1016/j.lfs.2023.122316 38035995
    [Google Scholar]
  12. Babaei A. Yazdi A.T. Ranji R. Bahadoran E. Taheri S. Nikkhahi F. Ghorbani S. Abbasi A. Therapeutic effects of exosomal miRNA-4731‐5p from adipose tissue-derived stem cells on human glioblastoma cells. Arch. Med. Res. 2024 55 7 103061 10.1016/j.arcmed.2024.103061 39098111
    [Google Scholar]
  13. Gholamzadeh Khoei S. Manoochehri H. Saidijam M. Systemic biological study for identification of miR-299-5p target genes in cancer. Meta Gene 2020 24 100655 10.1016/j.mgene.2020.100655
    [Google Scholar]
  14. Kiaheyrati N. Babaei A. Ranji R. Bahadoran E. Taheri S. Farokhpour Z. Cancer therapy with the viral and bacterial pathogens: The past enemies can be considered the present allies. Life Sci. 2024 349 122734 10.1016/j.lfs.2024.122734 38788973
    [Google Scholar]
  15. Lou G. Liu Y. Wu S. Xue J. Yang F. Fu H. Zheng M. Chen Z. The p53/miR-34a/SIRT1 positive feedback loop in quercetin-induced apoptosis. Cell. Physiol. Biochem. 2015 35 6 2192 2202 10.1159/000374024 25896587
    [Google Scholar]
  16. Gao J. Li N. Dong Y. Li S. Xu L. Li X. Li Y. Li Z. Ng S.S. Sung J.J. Shen L. Yu J. miR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer. Oncogene 2015 34 31 4142 4152 10.1038/onc.2014.348 25362853
    [Google Scholar]
  17. Shi X. Kaller M. Rokavec M. Kirchner T. Horst D. Hermeking H. Characterization of a p53/miR-34a/CSF1R/STAT3 feedback loop in colorectal cancer. Cell. Mol. Gastroenterol. Hepatol. 2020 10 2 391 418 10.1016/j.jcmgh.2020.04.002 32304779
    [Google Scholar]
  18. Li H. Rokavec M. Jiang L. Horst D. Hermeking H. Antagonistic effects of p53 and HIF1A on microRNA-34a regulation of PPP1R11 and STAT3 and hypoxia-induced epithelial to mesenchymal transition in colorectal cancer cells. Gastroenterology 2017 153 2 505 520 10.1053/j.gastro.2017.04.017 28435028
    [Google Scholar]
  19. Yamakuchi M. Lowenstein C.J. MiR-34, SIRT1, and p53: The feedback loop. Cell Cycle 2009 8 5 712 715 10.4161/cc.8.5.7753 19221490
    [Google Scholar]
  20. Gong J. Cong M. Wu H. Wang M. Bai H. Wang J. Que K. Zheng K. Zhang W. Yang X. Gong J. Shi H. Miao M. Yuan F. P53/miR-34a/SIRT1 positive feedback loop regulates the termination of liver regeneration. Aging 2023 15 6 1859 1877 10.18632/aging.203920 36988541
    [Google Scholar]
  21. Lin H.C. Kachingwe B.H. Lin H.L. Cheng H.W. Uang Y.S. Wang L.H. Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: A 6-year follow-up study. Pharmacotherapy 2014 34 1 36 45 10.1002/phar.1334 23864581
    [Google Scholar]
  22. Kheirandish M. Mahboobi H. Yazdanparast M. Kamal W. Kamal M.A. Anti-cancer effects of metformin: Recent evidences for its role in prevention and treatment of cancer. Curr. Drug Metab. 2018 19 9 793 797 10.2174/1389200219666180416161846 29663879
    [Google Scholar]
  23. Wang Y. Xu W. Yan Z. Zhao W. Mi J. Li J. Yan H. Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J. Exp. Clin. Cancer Res. 2018 37 1 63 10.1186/s13046‑018‑0731‑5 29554968
    [Google Scholar]
  24. Buckley C.E. O’Brien R.M. Nugent T.S. Donlon N.E. O’Connell F. Reynolds J.V. Hafeez A. O’Ríordáin D.S. Hannon R.A. Neary P. Kalbassi R. Mehigan B.J. McCormick P.H. Dunne C. Kelly M.E. Larkin J.O. O’Sullivan J. Lynam-Lennon N. Metformin is a metabolic modulator and radiosensitiser in rectal cancer. Front. Oncol. 2023 13 1216911 10.3389/fonc.2023.1216911 37601689
    [Google Scholar]
  25. Li J. Wang Y. Shen W. Zhang Z. Su Z. Guo X. Pei P. Hu L. Liu T. Yang K. Guo L. Mitochondria‐modulating liposomes reverse radio‐resistance for colorectal cancer. Adv. Sci. 2024 11 18 2400845 10.1002/advs.202400845 38520732
    [Google Scholar]
  26. Fernandes J.M. Jandrey E.H.F. Koyama F.C. Leite K.R.M. Camargo A.A. Costa É.T. Perez R.O. Asprino P.F. Metformin as an alternative radiosensitizing agent to 5-fluorouracil during neoadjuvant treatment for rectal cancer. Dis. Colon Rectum 2020 63 7 918 926 10.1097/DCR.0000000000001626 32229782
    [Google Scholar]
  27. Fawzy M.S. Ibrahiem A.T. AlSel B.T.A. Alghamdi S.A. Toraih E.A. Analysis of microRNA-34a expression profile and rs2666433 variant in colorectal cancer: A pilot study. Sci. Rep. 2020 10 1 16940 10.1038/s41598‑020‑73951‑y 33037254
    [Google Scholar]
  28. Roy S. Levi E. Majumdar A.P.N. Sarkar F.H. Expression of miR-34 is lost in colon cancer which can be re-expressed by a novel agent CDF. J. Hematol. Oncol. 2012 5 1 58 10.1186/1756‑8722‑5‑58 22992310
    [Google Scholar]
  29. Meng F. Yang M. Chen Y. Chen W. Wang W. miR-34a induces immunosuppression in colorectal carcinoma through modulating a SIRT1/NF-κB/B7-H3/TNF-α axis. Cancer Immunol. Immunother. 2021 70 8 2247 2259 10.1007/s00262‑021‑02862‑2 33492448
    [Google Scholar]
  30. Truong Do M. Gyun Kim H. Ho Choi J. Gwang Jeong H. Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1α/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radic. Biol. Med. 2014 74 21 34 10.1016/j.freeradbiomed.2014.06.010 24970682
    [Google Scholar]
  31. Sargolzaei J. Etemadi T. Alyasin A. The P53/microRNA network: A potential tumor suppressor with a role in anticancer therapy. Pharmacol. Res. 2020 160 105179 10.1016/j.phrs.2020.105179 32890739
    [Google Scholar]
  32. Hünten S. Siemens H. Kaller M. Hermeking H. The p53/microRNA network in cancer: experimental and bioinformatics approaches. Adv. Exp. Med. Biol. 2013 774 77 101 10.1007/978‑94‑007‑5590‑1_5 23377969
    [Google Scholar]
  33. Rokavec M. Li H. Jiang L. Hermeking H. The p53/miR-34 axis in development and disease. J. Mol. Cell Biol. 2014 6 3 214 230 10.1093/jmcb/mju003 24815299
    [Google Scholar]
  34. Elibol B. Kilic U. High levels of SIRT1 expression as a protective mechanism against disease-related conditions. Front. Endocrinol. 2018 9 614 10.3389/fendo.2018.00614 30374331
    [Google Scholar]
  35. Lin Z. Fang D. The roles of SIRT1 in cancer. Gen. Canc. 2013 4 3-4 97 104 10.1177/1947601912475079 24020000
    [Google Scholar]
/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
Bentham Science Publishers ; 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
Keywords: metformin ; microRNAs ; Colorectal cancer ; Sirtuin 1 ; cell proliferation

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