Abstract
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.
MeSH terms
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DNA-Binding Proteins / metabolism
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Genes, Reporter
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Humans
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Ligands
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Nuclear Proteins / metabolism
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PTEN Phosphohydrolase
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Pancreatic Neoplasms / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism*
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Prostaglandin D2 / analogs & derivatives*
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Prostaglandin D2 / chemistry
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Prostaglandin D2 / metabolism
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / metabolism
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Thiazoles / chemistry
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Thiazoles / metabolism
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Thiazolidinediones*
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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DNA-Binding Proteins
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Ligands
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Nuclear Proteins
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Proto-Oncogene Proteins
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Receptors, Cytoplasmic and Nuclear
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Recombinant Fusion Proteins
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Repressor Proteins
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Tumor Suppressor Proteins
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9-deoxy-delta-9-prostaglandin D2
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2,4-thiazolidinedione
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Prostaglandin D2