The PI3K pathway contributes to the invasive properties and apoptosis resistance that epitomize pancreatic cancers. PPARgamma is a ligand-activated transcription factor with anti-inflammatory and anti-tumor effects; the mechanisms of tumor suppression are unknown. The purpose of this study was to examine whether activation of PPARgamma can increase the expression of the tumor suppressor PTEN and inhibit PI3K activity. AsPC-1 human pancreatic cancer cells, transfected with a PPRE-luciferase construct, demonstrated increased luminescence following treatment with PPARgamma ligands, indicating the presence of functional PPARgamma protein. The selective PPARgamma ligand rosiglitazone increased PTEN expression in AsPC-1 cells; concurrent treatment with GW9662, which inhibits PPARgamma activation, prevented the increase in PTEN protein levels. Levels of phosphorylated Akt decreased as PTEN levels increased, indicating inhibition of PI3K activity. Taken together, our results suggest that activation of PPARgamma may represent a novel approach for the treatment of pancreatic cancer by increasing PTEN levels and inhibiting PI3K activity. (C) 2002 Elsevier Science (USA). All rights reserved.