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- Title
Peroxisome proliferator-activated receptor-? upregulates caveolin-1 and caveolin-2 expression in human carcinoma cells.
- Authors
Burgermeister, Elke; Tencer, Lilach; Liscovitch, Mordechai
- Abstract
Peroxisome proliferator-activated receptor-? (PPAR?) is a nuclear receptor for eicosanoids that promotes differentiation of human epithelial and mesenchymal cells in vitro and in vivo. PPAR? was proposed as a target for drug-induced differentiation therapy of cancer. Caveolin-1 is a constituent of plasma membrane caveolae in epithelial cells that is often downregulated upon oncogenic transformation. Caveolin-1 has growth-inhibitory activities and its disruption is sufficient to induce transformation in fibroblasts. Herein we have tested the hypothesis that caveolins are transcriptional target genes for PPAR?. In human HT-29 colon carcinoma cells, thiazolidinedione PPAR? ligands increased the levels of caveolin-1 and caveolin-2 proteins two to fivefold in a concentration-dependent manner within 24?h. In human MCF-7 breast adenocarcinoma cells, nonthiazolidinedione PPAR? ligands elevated caveolin-2 protein three to fourfold, while the thiazoli-dinediones were less effective. Caveolin-1 mRNA levels were found to be upregulated by PPAR? ligands already after 3?h in both the cell lines. Ectopic expression of a dominant-negative PPAR? construct attenuated ligand-induced upregulation of caveolins in both HT-29 and HEK-293T cells, indicating that ligand action is mediated by PPAR?. Ligand-treated MCF-7 cells exhibited a differentiated phenotype, as evinced by analysis of cell-specific differentiation markers: protein levels of maspin were elevated and perinuclear lipid droplets accumulated. In contrast, in HT-29 cells, caveolin expression was not correlated with differentiation. Interestingly, PPAR? partially cofractionated in lipid rafts and could be coimmunoprecipitated from cell lysates with caveolin-1, indicating that PPAR? and caveolin-1 may coexist in a complex. Our data indicate that PPAR? participates in the regulation of caveolin gene expression in human carcinoma cells and suggest that caveolin-1 may mediate some of the phenotypic changes induced by this...
- Subjects
PEROXISOMES; NUCLEAR receptors (Biochemistry); EICOSANOIC acid derivatives; MESENCHYME; MULTIDRUG resistance
- Publication
Oncogene, 2003, Vol 22, Issue 25, p3888
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1206625