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Metformin induces cytotoxicity by down-regulating thymidine phosphorylase and excision repair cross-complementation 1

Jen-Chung Ko1, Yu-Ching Huang, Huang-Jen Chen

  • 1Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan.

Basic & Clinical Pharmacology & Toxicology
|February 1, 2013
PubMed

Insights

Metformin, an antidiabetic drug, inhibits non-small cell lung cancer (NSCLC) growth by reducing thymidine phosphorylase (TP) and Excision repair cross-complementation 1 (ERCC1) expression. This mechanism involves the MEK/ERK pathway, offering potential therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Metformin exhibits anti-cancer properties, but its molecular mechanisms remain unclear.
  • High thymidine phosphorylase (TP) and Excision repair cross-complementation 1 (ERCC1) expression correlate with poor prognosis in many cancers.
  • Non-small cell lung cancer (NSCLC) is a major cause of cancer-related mortality.

Purpose of the Study:

  • To investigate the role of TP and ERCC1 in metformin-induced cytotoxicity in NSCLC.
  • To elucidate the molecular pathways mediating metformin's anti-cancer effects.

Main Methods:

  • Utilized A549 and H1975 human NSCLC cell lines.
  • Assessed protein and mRNA levels of TP and ERCC1 following metformin treatment.
  • Investigated the involvement of the MEK/ERK signaling pathway.
  • Employed siRNA to inhibit TP and ERCC1 expression.
  • Used constitutively active MEK1 (MEK1-CA) vectors and arachidin-1.

Main Results:

  • Metformin dose- and time-dependently decreased TP and ERCC1 protein and mRNA levels.
  • This decrease was mediated by down-regulation of phosphorylated MEK1/2-ERK1/2.
  • Enforced MEK1-CA expression restored TP, ERCC1 levels, and cell viability.
  • siRNA-mediated inhibition of TP and ERCC1 enhanced metformin's cytotoxic effects.
  • Arachidin-1 augmented metformin's cytotoxicity, an effect dependent on MEK/ERK signaling.

Conclusions:

  • Metformin induces cytotoxicity in NSCLC cells by down-regulating TP and ERCC1 expression.
  • The MEK/ERK pathway plays a critical role in mediating metformin's effects on TP and ERCC1.
  • Targeting TP and ERCC1, potentially in combination with metformin, could be a therapeutic strategy for NSCLC.

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