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.
Highlights
Defining novel treatment options of melanoma is still a challenge and the identification of new agents is vital due to the increasing incidence and poor prognosis [1,2]
We investigated the anti-proliferative effects of peroxisome proliferatoractivated receptor-c (PPARc) ligands ciglitazone, troglitazone and 15d-PGJ2 and the PPARa ligand WY-14643 on four melanoma cell lines (A375, M24met, 1205Lu and MelJuso)
While recent reports indicate antiproliferative effects of these drugs in several cancer cells including melanoma, this is the first investigation of PPARc ligand effects including both melanoma cells as well as melanoma-associated stroma cells such as fibroblasts and endothelial cells
Summary
Defining novel treatment options of melanoma is still a challenge and the identification of new agents is vital due to the increasing incidence and poor prognosis [1,2]. PPARs are ligand-activated transcription factors of the nuclear hormone receptor superfamily comprising three subtypes: PPARa, PPARc, and PPARd/b and are characterized by distinct functions, ligand specificities and tissue distribution [4]. The three high affinity ligands directly regulate cyclin D1 and p21 and the multifunctional protein ß-catenin [14,15] The latter observation implies that PPARc ligands may be able to interfere with the metastatic process [16]. The PPARc agonists ciglitazone, troglitazone and 15d-PGJ2 and the PPARa ligand WY-14643 were tested on four melanoma cell lines (A375, M24met, 1205Lu and MelJuso) to generalize our findings. Our study indicates that 15d-PGJ2 is a potent anti-tumorigenic compound by interfering with melanoma cell proliferation, metastasis and affecting the melanoma associated stroma
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