Cilostazol inhibits TGF-α-induced migration of hepatocellular carcinoma cells by activating PPARγ

Related Experiment Video

Updated: May 28, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

Rie Matsushima-Nishiwaki1, Haruhiko Tokuda2, Osamu Kozawa1

  • 1Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan.

Biochemical and Biophysical Research Communications
|May 26, 2026
PubMed

Insights

Phosphodiesterase (PDE) inhibitors, cilostazol and dipyridamole, suppress hepatocellular carcinoma (HCC) cell migration by activating peroxisome proliferator-activated receptor γ (PPARγ) and inhibiting the AKT pathway, independent of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hepatocellular carcinoma (HCC) is a prevalent cancer with high mortality.
  • Previous research indicated cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) activation suppresses transforming growth factor (TGF)-α-induced migration in HCC cells.
  • The role of phosphodiesterase (PDE) inhibitors in modulating HCC cell migration requires further investigation.

Purpose of the Study:

  • To investigate the effects of cilostazol, a PDE inhibitor, on TGF-α-induced migration of HCC cells.
  • To elucidate the underlying molecular mechanisms, including the involvement of cAMP/PKA, peroxisome proliferator-activated receptor γ (PPARγ), and AKT signaling pathways.

Main Methods:

  • Utilized human-derived HCC cell line (HuH7).
  • Administered cilostazol, dipyridamole (PDE inhibitors), ciglitazone, pioglitazone (PPARγ activators), and GW9662 (PPARγ inhibitor).
  • Assessed cell migration, intracellular cAMP levels, PKA activity, and activation of PPARγ, AKT, and epidermal growth factor receptor (EGFR) signaling pathways.

Main Results:

  • Cilostazol and dipyridamole significantly inhibited TGF-α-induced migration of HuH7 cells.
  • Neither PDE inhibitor increased intracellular cAMP levels or affected TGF-α-induced migration in the presence of a PKA inhibitor.
  • Cilostazol and dipyridamole stimulated PPARγ activation, and their inhibitory effects were blocked by GW9662.
  • PPARγ activators also inhibited TGF-α-induced migration.
  • Cilostazol, dipyridamole, and PPARγ activators suppressed TGF-α-induced AKT activation without affecting EGFR activation.

Conclusions:

  • Cilostazol and dipyridamole inhibit TGF-α-induced HCC cell migration.
  • The mechanism involves the activation of PPARγ and subsequent suppression of the AKT signaling pathway, independent of the cAMP/PKA pathway.
  • These findings suggest potential therapeutic strategies for HCC targeting the PPARγ-AKT axis.
Keywords:
AKTCilostazolHCCMigrationPPARγTGF-α

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