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

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and remains a public health problem with high mortality. We have previously reported that activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) suppresses transforming growth factor (TGF)-α-induced migration of HCC cells. In the present study, we investigated whether cilostazol, a phosphodiesterase (PDE) inhibitor, affects the TGF-α-induced migration of HCC cells. Cilostazol significantly inhibited TGF-α-induced migration of human-derived HCC cells, HuH7. Dipyridamole, another PDE inhibitor, also significantly suppressed the cell migration induced by TGF-α. However, neither cilostazol nor dipyridamole increased the intracellular concentrations of cAMP under TGF-α-stimulation. Furthermore, TGF-α-induced HCC cell migration, which was inhibited by cilostazol and dipyridamole, was not affected by a PKA inhibitor. On the other hand, cilostazol and dipyridamole stimulated the activation of peroxisome proliferator-activated receptor γ (PPARγ) in HuH7 cells. We also found that PPARγ activators, ciglitazone and pioglitazone, significantly inhibited the TGF-α-induced migration of HuH7 cells. The inhibitory effects of cilostazol and dipyridamole on the migration of HuH7 cells were blocked by GW9662, an inhibitor of PPARγ. We have shown that AKT is involved in the TGF-α-induced HuH7 cell migration. The PPARγ activators reduced the TGF-α-induced AKT activation without affecting the EGFR activation. Cilostazol and dipyridamole also inhibited the activation of AKT but not EGFR. Taken together, these results strongly suggest that cilostazol and dipyridamole inhibit TGF-α-induced HCC cell migration by suppressing the AKT pathway through PPARγ activation.