In the present study, we examined a role of mitogen-activated protein kinases (MAPKs), extracellular signal-related kinase (ERK), c-Jun NI-terminal protein kinase, and p38 MAPK in troglitazone-induced inhibition of cell growth in human pancreatic cancer cells. Among the three kinases, troglitazone specifically inhibited the phosphorylation of ERK1/2 in a dose- and time-dependent manner. Troglitazone also down-regulated the protein expression of mitogen-activated protein kinase kinase (MEK) 1/2, an upstream molecule that regulates ERK phosphorylation. Treatment of human pancreatic cancer cells with specific MEK inhibitor, PD98059 or U0126, inhibited ERK1/2 phosphorylation and cell growth. These results Suggest for the first time that the inhibition of the MEK1/2-ERK1/2 may be implicated in the growth inhibitory effect by troglitazone in human pancreatic cancer cells. signaling pathway (c) 2005 Elsevier Inc. All rights reserved.