The activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to induce growth arrest and differentiation of various cancer cells. In the current study, we investigated the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the expression of PPAR gamma and proliferation of A549 cells. TPA elicited a dose- and time-dependent increase in PPAR gamma mRNA and protein levels. PPAR gamma expression in response to TPA was attenuated by pretreatment with bisindolylmaleimide 1, N-acetyl-L-cysteine (NAC) and PD98059. TPA-induced protein kinase C (PKC) activation was linked to the generation of reactive oxygen species (ROS), both of which were indispensable for PPAR gamma expression in A549 cells. Pretreatment with bisindolylmaleimide I or NAC blocked TPA-induced phosphorylation of extracellular signal-regulated kinase (ERK), suggesting that ERK-mediated signaling is also involved in the induction of PPAR gamma. Furthermore, the growth inhibitory effect of troglitazone was significantly potentiated by prolonged incubation with TPA and was attenuated in the presence of GW9662, a specific inhibitor of PPAR gamma. These effects were associated with an induction of cell cycle arrest at G(0)/G(1) phase, which was accompanied by the induction of p21(Wafl/Cip1) expression and decreased cyclin D1 expression. Taken together, these observations indicate that TPA synergizes with PPAR gamma ligand to inhibit cell growth through up-regulation of PPAR gamma expression. (c) 2006 Elsevier Inc. All rights reserved.