Troglitazone attenuates epidermal growth factor receptor signaling independently of peroxisome proliferator-activated receptor in PC-3 cells.

The role of the peroxisome proliferator-activated receptor-γ (PPARγ) in cell differentiation, cell cycle arrest and apoptosis has attracted increasing attention. Troglitazone (TGZ), a thiazolidinedione ligand of PPARγ, has been recently described as possessing antitumoral properties. We studied the effects of TGZ on proliferation, growth arrest and apoptosis in PC-3 prostate carcinoma cells and its interaction with the signaling pathways of the activated EFG receptor (EGFR). We observed that TGZ, in a dose- and time-dependent manner, inhibited the growth of PC-3 cells independent of PPARγ. In addition, TGZ induced cell cycle arrest and apoptosis. We demonstrated that cell proliferation was stimulated by EFG in a dose- and time-dependent manner and was inhibited by TGZ. The analysis of the main intracellular signaling pathways downstream of the activated EGFR, PI3K-Akt, ERK1/2 cascades and IκBα revealed that TGZ reduced the phosphorylation levels of EGFR and of their downstream inter-mediators which mediate EGF stimulated proliferation. In conclusion, simultaneous targeting of EGFR, PI3K-Akt, ERK1/2 and NF-κB by TGZ could be the molecular mechanism by which TGZ exerts its additive inhibitory effects on PC-3 cell proliferation.