科研之友
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摘要
Background and PurposeDespite 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. %26lt;br%26gt;Experimental ApproachThe 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. %26lt;br%26gt;Key ResultsSimvastatin was shown to activate a stress cascade, leading to the synthesis of 15-deoxy-12,14-PGJ(2) (15d-PGJ(2)), in a p38- and COX-2-dependent manner. Significant concentrations of 15d-PGJ(2) 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-PGJ(2) synthesis, abolished the apoptotic effect of simvastatin. Moreover, 15d-PGJ(2) 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- and amplified the apoptotic response. %26lt;br%26gt;Conclusions and ImplicationsWe characterized simvastatin-induced activation of the 15d-PGJ(2)/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-PGJ(2) in metastatic melanoma.
- 出版日期2014-12
