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Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal

Mary L Fay1, Chris Nicol1,2, Christine Orr2

  • 1Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen's University, Kingston, ON K7L 3N6, Canada.

Current Oncology (Toronto, Ont.)
|March 26, 2025
PubMed

Insights

Metformin may protect against colorectal cancer (CRC) by altering gene expression, downregulating TMEM132 and upregulating SCNN1A. This suggests the unfolded protein response enhances apoptosis, offering new therapeutic targets for CRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Type 2 diabetes is a known risk factor for colorectal cancer (CRC) development and progression.
  • Metformin treatment in diabetic CRC patients is associated with improved clinical outcomes compared to other management strategies.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying metformin's protective effects in colorectal cancer.
  • To identify specific molecular features that differentiate metformin-treated diabetic CRC patients from diet-controlled ones.

Main Methods:

  • Targeted transcriptomic analysis of 272 primary CRC tissue samples.
  • Application of a supervised learning algorithm to identify discriminating molecular features.
  • Analysis of gene expression patterns (TMEM132, SCNN1A) and apoptotic protein levels (sFas).

Main Results:

  • Downregulation of TMEM132 observed in metformin-treated CRC samples and in non-diabetic patients with good survival.
  • Upregulation of SCNN1A observed in metformin-treated CRC samples and in non-diabetic patients with good survival.
  • Downregulation of the antiapoptotic protein sFas in metformin-treated samples compared to diet-controlled samples.

Conclusions:

  • Metformin's CRC-protective effects may involve the unfolded protein response, leading to enhanced apoptosis.
  • TMEM132, SCNN1A, and sFas represent potential molecular targets for novel CRC therapies.
  • Further investigation into these pathways could lead to improved treatment strategies for colorectal cancer.
Keywords:
colorectal cancermetformintype 2 diabetesunfolded protein response

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