Proteome analysis identified the PPARγ ligand 15d-PGJ2 as a novel drug inhibiting melanoma progression and interfering with tumor-stroma interaction

• Published in: PloS one Vol. 7; no. 9; p. e46103
• Main Authors: Paulitschke, Verena, Gruber, Silke, Hofstätter, Elisabeth, Haudek-Prinz, Verena, Klepeisz, Philipp, Schicher, Nikolaus, Jonak, Constanze, Petzelbauer, Peter, Pehamberger, Hubert, Gerner, Christopher, Kunstfeld, Rainer
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.09.2012; Public Library of Science (PLoS)
• Subjects: Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Biology; Cancer; Cell adhesion & migration; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chaperones; Chemistry; Chromans - pharmacology; Dermatology; Drug dosages; Endothelial cells; Fibroblasts; Gel electrophoresis; Glucose metabolism; Heat shock proteins; Homeostasis; Hsp90 protein; Humans; Immunoprecipitation; Kinases; Ligands; Lipid metabolism; Matrix metalloproteinase; Medicine; Melanoma; Melanoma - metabolism; Metabolism; Metalloproteinase; Metastases; Metastasis; Paxillin; Peroxisome proliferator-activated receptors; PPAR gamma - agonists; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Protein biosynthesis; Protein synthesis; Protein transport; Proteins; Proteome - metabolism; Proteomes; Pyrimidines - pharmacology; Receptors; Rodents; Stroma; Studies; Thiazolidinediones - pharmacology; Tumor suppressor genes; Tumors; Two dimensional analysis; Austria
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0046103

Peroxisome proliferator-activated receptors (PPARs) have been originally thought to be restricted to lipid metabolism or glucose homeostasis. Recently, evidence is growing that PPARγ ligands have inhibitory effects on tumor growth. To shed light on the potential therapeutic effects on melanoma we tested a panel of PPAR agonists on their ability to block tumor proliferation in vitro. Whereas ciglitazone, troglitazone and WY14643 showed moderate effects on proliferation, 15d-PGJ2 displayed profound anti-tumor activity on four different melanoma cell lines tested. Additionally, 15d-PGJ2 inhibited proliferation of tumor-associated fibroblasts and tube formation of endothelial cells. 15d-PGJ2 induced the tumor suppressor gene p21, a G(2)/M arrest and inhibited tumor cell migration. Shot gun proteome analysis in addition to 2D-gel electrophoresis and immunoprecipitation of A375 melanoma cells suggested that 15d-PGJ2 might exert its effects via modification and/or downregulation of Hsp-90 (heat shock protein 90) and several chaperones. Applying the recently established CPL/MUW database with a panel of defined classification signatures, we demonstrated a regulation of proteins involved in metastasis, transport or protein synthesis including paxillin, angio-associated migratory cell protein or matrix metalloproteinase-2 as confirmed by zymography. Our data revealed for the first time a profound effect of the single compound 15d-PGJ2 on melanoma cells in addition to the tumor-associated microenvironment suggesting synergistic therapeutic efficiency.