Article: article from journal or magazin.
Differential regulation of vascular endothelial growth factor expression by peroxisome proliferator-activated receptors in bladder cancer cells.
Journal of Biological Chemistry
The growth of any solid tumor depends on angiogenesis. Vascular endothelial growth factor (VEGF) plays a prominent role in vesical tumor angiogenesis regulation. Previous studies have shown that the peroxisome proliferator-activated receptor gamma (PPARgamma) was involved in the angiogenesis process. Here, we report for the first time that in two different human bladder cancer cell lines, RT4 (derived from grade I tumor) and T24 (derived from grade III tumor), VEGF (mRNA and protein) is differentially up-regulated by the three PPAR isotypes. Its expression is increased by PPARalpha, beta, and gamma in RT4 cells and only by PPARbeta in T24 cells via a transcriptional activation of the VEGF promoter through an indirect mechanism. This effect is potentiated by an RXR (retinoid-X-receptor), selective retinoid LG10068 providing support for a PPAR agonist-specific action on VEGF expression. While investigating the downstream signaling pathways involved in PPAR agonist-mediated up-regulation of VEGF, we found that only the MEK inhibitor PD98059 reduced PPAR ligand-induced expression of VEGF. These data contribute to a better understanding of the mechanisms by which PPARs regulate VEGF expression. They may lead to a new therapeutic approach to human bladder cancer in which excessive angiogenesis is a negative prognostic factor.
1-Phosphatidylinositol 3-Kinase/physiology, Carrier Proteins/physiology, Culture Media, Conditioned, Endothelial Growth Factors/analysis, Endothelial Growth Factors/genetics, Fatty Acid-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Lymphokines/analysis, Lymphokines/genetics, Mitogen-Activated Protein Kinases/physiology, Neoplasm Proteins, RNA, Messenger/analysis, Receptors, Cytoplasmic and Nuclear/genetics, Receptors, Cytoplasmic and Nuclear/physiology, Transcription Factors/genetics, Transcription Factors/physiology, Tumor Cells, Cultured, Tumor Suppressor Proteins, Urinary Bladder Neoplasms/metabolism, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, p38 Mitogen-Activated Protein Kinases
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