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The antitumor effects of metformin are potentially mediated through LPA receptor inhibition

Koichi Sato1, Hideaki Ogasawara2, Yuichi Ikeda2

  • 1Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan.

Diabetes Research and Clinical Practice
|March 12, 2025
PubMed
Abstract

Insights

Metformin, a diabetes drug, may fight tumors by blocking lysophosphatidic acid (LPA) receptor signaling. This action inhibits cell migration, potentially contributing to metformin's antitumor effects.

Area of Science:

  • Cellular biology
  • Pharmacology
  • Oncology

Background:

  • Metformin exhibits antitumor properties, but its precise mechanisms, especially concerning G protein-coupled receptors (GPCRs), are not fully understood.
  • GPCRs play crucial roles in cellular signaling pathways relevant to cancer progression.

Purpose of the Study:

  • To investigate the impact of metformin on GPCR signaling pathways.
  • To elucidate the role of lysophosphatidic acid (LPA) receptors in metformin's cellular effects.
  • To determine if metformin's inhibition of LPA receptor signaling contributes to its antitumor activity.

Main Methods:

  • Screened 200 GPCRs in metformin-treated cells.
  • Assessed metformin's effect on LPA-induced intracellular calcium (Ca2+) mobilization in cells expressing LPA receptors (LPAR1, LPAR2, LPAR3).
  • Evaluated the influence of metformin and a Gq/11 inhibitor on LPA-stimulated cell adhesion and migration.

Main Results:

  • Metformin suppressed signaling through multiple GPCRs, notably LPA receptors.
  • Metformin significantly reduced LPA-induced Ca2+ mobilization in LPAR1, LPAR2, and LPAR3-transfected cells.
  • Metformin attenuated LPA-driven cell adhesion and migration, an effect comparable to a Gq/11 inhibitor but distinct from epidermal growth factor-induced migration.

Conclusions:

  • Metformin inhibits LPA receptor signaling.
  • Suppression of LPAR3-mediated cell migration by metformin is a key finding.
  • These findings suggest that inhibiting LPA receptor signaling may be a mechanism underlying metformin's antitumor effects.
Keywords:
Antitumor effectCell migrationG protein-coupled receptorLysophosphatidic acidMetforminintracellular Ca(2+) mobilization

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