Autocrine amplification loop in statin-induced apoptosis of human melanoma cells

Abstract

Background and purpose: Beside their cholesterol lowering effect, statins exert pleiotropic effects, which include antiinflammatory, immunosuppressive and anti-proliferative actions. In higher concentrations, statins trigger apoptosis in primary cells and tumour cells. In particular, melanoma cells have been found to be susceptible to statin-induced apoptosis, although only after longer incubation times. The molecular mechanisms behind this delayed drug-induced apoptosis are still unclear. Experimental approach: The human melanoma A375 and 518A2 cell lines were exposed to various statins in a timedependent and dose-dependent manner, and indicators of apoptosis, caspase activity and individual apoptotic pathways were analysed for 3-hydroxy-3-methylglutaryl- coenzyme A reductase dependent and independent effects. Key results: Kinetic analysis of statin-induced apoptosis revealed an apoptotic burst for exposure times longer than 24 h. While the extrinsic pathway was not activated within 24 h, longer incubation times corroborated amplification of the mitochondrial pathway with significant activation of caspase 8. Continuous refreshing of the simvastatin-containing medium abrogated the mitochondrial amplification loop via caspase 8. Moreover, conditional medium, supplemented with mevalonic acid in order to nullify a possible contamination by statins, significantly triggered caspase 8 activity. Fas ligand was excluded as a possible candidate to account for the statin-induced autocrine amplification loop. Conclusions and implications: Simvastatin and atorvastatin are capable of triggering an 'autocrine' suicide factor, which amplifies apoptosis via the extrinsic pathway in human melanoma cells. This pro-apoptotic stimulus implies possible therapeutic potential and may guide feasibility for more potent statins in anti-cancer strategies. © 2009 The British Pharmacological Society All rights reserved.