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

Ensiyeh Bahadoran1, Yazdan Zafari2, Ali Homaei3

  • 1School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.

Current Radiopharmaceuticals
|February 7, 2025
PubMed
Abstract

Insights

Metformin enhances radiation sensitivity in colon cancer by modulating the p53/miR-34a/SIRT1 pathway. This involves downregulating SIRT1 and upregulating miR-34a, increasing apoptosis and reducing viability in resistant cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Metformin is known to induce radiosensitivity in various cancer cells, including colorectal cancer.
  • The precise molecular mechanisms behind metformin's radiosensitizing effects remain largely unknown.
  • This study focuses on elucidating the role of the p53/miR-34a/SIRT1 pathway in metformin-induced radiosensitivity in colon cancer.

Purpose of the Study:

  • To investigate the involvement of the p53/miR-34a/SIRT1 pathway in the radiosensitivity of colon cancer cells treated with metformin.
  • To determine how metformin affects the expression of miR-34a and SIRT1 in radioresistant colon cancer cells.
  • To assess the impact of metformin on cell proliferation and apoptosis in the context of this pathway.

Main Methods:

  • Generated radioresistant colorectal cancer cell lines (SW480 and SW620) via 50 Gy radiation.
  • Treated resistant cells with 50 μM metformin and compared with untreated controls.
  • Quantified miR-34a and SIRT1 expression using Quantitative Real-time PCR.
  • Assessed cell viability and apoptosis via CCK-8 assay and flow cytometry.
  • Analyzed protein expression, including acetylated P53, using Western blot analysis.

Main Results:

  • Radiation-resistant cells exhibited downregulated miR-34a and upregulated SIRT1 expression.
  • Metformin treatment significantly decreased cell viability and increased apoptosis in resistant cells.
  • Metformin reversed the expression changes, upregulating miR-34a and downregulating SIRT1.
  • Western blot confirmed increased acetylated P53 levels post-metformin treatment.
  • The effects of metformin were abrogated by SIRT1 inhibitors or miR-34a overexpressing plasmids.

Conclusions:

  • Metformin enhances radiosensitivity in colorectal cancer cells.
  • The p53/miR-34a/SIRT1 pathway is a key mechanism mediating metformin's radiosensitizing effects.
  • Modulation of this pathway by metformin leads to increased apoptosis and reduced viability in resistant cancer cells.
Keywords:
Colorectal cancerapoptosis.cell proliferationmetforminmicroRNAsp53 pathwayradiosensitizationsirtuin 1

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