Cellular and molecular consequences of peroxisome proliferator-activated receptor-gamma activation in ovarian cancer cells.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor. In addition to its canonical role in lipid and glucose metabolism, PPAR-gamma controls cell proliferation, death, and differentiation in several tissues. Here we have examined the expression of PPAR-gamma in ovarian tumors and the cellular and molecular consequences of its activation in ovarian cancer cells. PPAR-gamma was expressed in a large number of epithelial ovarian tumors and cell lines. The PPAR-gamma ligand ciglitazone inhibited the growth and clonogenic survival of ovarian cancer cells, inducing cell cycle arrest and cell death. Growth inhibition by ciglitazone was reversed by the PPAR-gamma antagonist GW9662, indicating the involvement of PPAR-gamma-dependent mechanisms. Microarray-based gene profiling revealed complex changes in the transcriptional program of ovarian cancer cells on treatment with ciglitazone and identified multiple pathways that may contribute to PPAR-gamma ligands' antitumor activity. Genes upregulated by ciglitazone were predominantly associated with metabolic, differentiation, and tumor-suppressor pathways, whereas downregulated genes were involved in cell proliferation, cell cycle, cell organization, and steroid biosynthesis. Collectively, our data indicate that PPAR-gamma activation by selective agonists is a valid strategy for ovarian cancer therapy and prevention, and should be tested alone and in combination with other anticancer drugs.
Vignati
Sara
S
Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Albertini
Veronica
V
Rinaldi
Andrea
A
Kwee
Ivo
I
Riva
Cristina
C
Oldrini
Rita
R
Capella
Carlo
C
Bertoni
Francesco
F
Carbone
Giuseppina M
GM
Catapano
Carlo V
CV
D002453:Cell Cycle; D002470:Cell Survival; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008024:Ligands; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; C039671:ciglitazone