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Proteome Analysis Identified the PPARγ Ligand 15d-PGJ2 as a Novel Drug Inhibiting Melanoma Progression and Interfering with Tumor-Stroma Interaction

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Abstract

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 G2/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.

PLoS ONE: Research Article, published 25 Sep 2012 10.1371/journal.pone.0046103

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Acknowledgements

We thank Dr. Ichiro Okamoto and Dr. Oliver Schanab for management of patient sample collection, Dr. Mario Mikula and Dr. Alexander Swoboda for isolation of primary cells, Andrea Holzweber, Editha Bayer, Karin Neumüller and Barbara Pratscher for technical assistance and Johannes Griss for bioinformatic support. We thank DI Thomas Mohr for valuable help with the tube formation assay.

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Authors and Affiliations

  1. Dept. of Dermatology, Medical University of Vienna, Vienna, Austria

    Verena Paulitschke, Silke Gruber, Elisabeth Hofstätter, Nikolaus Schicher, Constanze Jonak, Peter Petzelbauer, Hubert Pehamberger & Rainer Kunstfeld

  2. Dept. of Medicine I, Medical University of Vienna, Vienna, Austria

    Verena Haudek-Prinz, Philipp Klepeisz & Christopher Gerner

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  1. Verena Paulitschke
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  2. Silke Gruber
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Correspondence to Verena Paulitschke .

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  1. , Department of Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93042, Germany

    Albrecht Reichle

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Paulitschke, V. et al. (2013). Proteome Analysis Identified the PPARγ Ligand 15d-PGJ2 as a Novel Drug Inhibiting Melanoma Progression and Interfering with Tumor-Stroma Interaction. In: Reichle, A. (eds) Evolution-adjusted Tumor Pathophysiology:. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6866-6_8

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