Autocrine secretion of 15d‐PGJ₂ mediates simvastatin‐induced apoptotic burst in human metastatic melanoma cells

Abstract

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. 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. KEY RESULTSSimvastatin 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 AND IMPLICATIONSWe 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. Abbreviations15d-PGJ2, 15-deoxy-12,14-PGJ2; FABP5, fatty acid-binding protein

Response to letter by Tsikas et al.

“…e l s e v i e r . c o m / l o c a t e / i j c a r d PGJ 2 with ROS production in different cellular systems at lower (95-160 nM) [17] as well as higher concentrations (1-20 μM) [5,18,19]. We agree with Tsikas et al [1] on their view that direct therapeutic targeting of 15d-PGJ 2 would be a difficult task.…”

Tocilizumab unmasks a stage-dependent interleukin-6 component in statin-induced apoptosis of metastatic melanoma cells

“…This observation provides a possible explanation for the facilitation of apoptosis triggered by coadministration with simvastatin (Figs 3 and 4 d). An additional argument is provided by our recent observation that simvastatin triggers the synthesis of the prostaglandin, 15d-PGJ 2 , which is an endogenous ligand of the peroxisome proliferator-activated receptors γ (PPARγ) 36 . Moreover, the fatty acid-binding protein 5, the lipid chaperon for 15d-PGJ 2 , is strongly upregulated in simvastatin-treated A375 and 518A2 cells and activates the PPARγ ligand.…”

Epigenetic marks responsible for cadmium-induced melanoma cell overgrowth

“…2 and 3), highlight the relevance of such a mechanism in this tumor. Recent literature evidences highlight the relevance of the intrinsic apoptosis pathway in uveal melanoma (Bi et al, 2013;Cui et al, 2012) and the pivotal role of caspase 8 in inducing the apoptotic burst in human metastatic skin melanoma cells (Wasinger et al, 2014). This latter mechanism has been so well ascertained as to encourage the usage of drugs able to activate the extrinsic apoptosis pathway in melanoma (Romano et al, 2013).…”