title: Autocrine secretion of 15d-PGJ2 mediates simvastatin-induced apoptotic burst in human metastatic melanoma cells.
abstract: OBJECTIVE
  Despite new therapeutic approaches, metastatic melanomas still have a poor prognosis. Statins reduce low-density lipoprotein cholesterol and exert anti-inflammatory and anti-proliferative actions. We have recently shown that simvastatin triggers an apoptotic burst in human metastatic melanoma cells by the synthesis of an autocrine factor.
  
  
  METHODS
  The current in vitro study was performed in human metastatic melanoma cell lines (A375, 518a2) and primary human melanocytes and melanoma cells. The secretome of simvastatin-stressed cells was analysed with two-dimensional difference gel electrophoresis and MS. The signalling pathways involved were analysed at the protein and mRNA level using pharmacological approaches and siRNA technology.
  
  
  RESULTS
  Simvastatin was shown to activate a stress cascade, leading to the synthesis of 15-deoxy-12,14-PGJ2 (15d-PGJ2 ), in a p38- and COX-2-dependent manner. Significant concentrations of 15d-PGJ2 were reached in the medium of melanoma cells, which were sufficient to activate caspase 8 and the mitochondrial pathway of apoptosis. Inhibition of lipocalin-type PGD synthase, a key enzyme for 15d-PGJ2 synthesis, abolished the apoptotic effect of simvastatin. Moreover, 15d-PGJ2 was shown to bind to the fatty acid-binding protein 5 (FABP5), which was up-regulated and predominantly detected in the secretome of simvastatin-stressed cells. Knockdown of FABP5 abolished simvastatin-induced activation of PPAR-γ and amplified the apoptotic response.
  
  
  CONCLUSIONS
  We characterized simvastatin-induced activation of the 15d-PGJ2 /FABP5 signalling cascades, which triggered an apoptotic burst in melanoma cells but did not affect primary human melanocytes. These data support the rationale for the pharmacological targeting of 15d-PGJ2 in metastatic melanoma.
authors.affiliation: Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Wasinger
authors.forename: Martin
authors.initials: M
authors.lastname: Künzl
authors.forename: Christoph
authors.initials: C
authors.lastname: Minichsdorfer
authors.forename: Christoph
authors.initials: C
authors.lastname: Höller
authors.forename: Maria
authors.initials: M
authors.lastname: Zellner
authors.forename: Martin
authors.initials: M
authors.lastname: Hohenegger
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication; D053181:Caspase 8 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050556:Fatty Acid-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors; D054834:Lipocalins / Q000037:antagonists & inhibitors; D008544:Melanocytes / Q000187:drug effects* / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D009362:Neoplasm Metastasis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: C477819:15-deoxyprostaglandin J2; C493412:FABP5 protein, human; D050556:Fatty Acid-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054834:Lipocalins; D019821:Simvastatin; C505530:CASP8 protein, human; D053181:Caspase 8; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2
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