Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells

In this study, we investigated the effects of troglitazone and ciglitazone on the mRNA expression of VEGF and its receptors in human NSCLC cell lines, RERF-LC-AI, SK-MES-1, PC-14, and A549. These mRNA expressions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also studied the effect of Je-11, a VEGF inhibitor, on the growth of these cells.In NSCLC cells, thiazolidinediones increased the mRNA expression of VEGF and neuropilin-1, but not that of other receptors such as fms-like tyrosine kinase and kinase insert domain receptor-1. Furthermore, the PPARγ antagonist GW9662 completely reversed this thiazolidinedione-induced increase in VEGF expression. Furthermore, the addition of VEGF inhibitors into the culture medium resulted in the reversal of thiazolidinedione-induced growth inhibition.Our results indicated that thiazolidinediones enhance VEGF and neuropilin-1 expression and induce the inhibition of cell growth. We propose the existence of a pathway for arresting cell growth that involves the interaction of thiazolidinedione-induced VEGF and neuropilin-1 in NSCLC.Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of ligand-activated transcription factors. PPARγ is an intracellular sensor for fatty acids and fatty acid derivatives, which in turn act as endogenous ligands for PPARγ. PPARγ and its ligand activators regulate several lipid and glucose metabolism pathways [1].In humans, PPARγ is expressed in multiple tissues, including the breast, colon, prostate, lung, placenta, and pituitary tissues [2-5]. PPARγ activation is antiproliferative by virtue of its differentiation-promoting effects. For example, ligands activating PPARγ were effective in arresting the growth of dedifferentiated tumor cells in multiple tumor types [2,4-9], and they promoted differentiation of tumor cells and inhibited spontaneous metastasis in a xenograft model [7]. However, the mechanism by which PPARγ arres