Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin.

Autor:	Cervia D; Department for Innovation in Biological, Agro-food and Forest Systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy.; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy., Assi E; Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.; Present address: Division of Experimental Oncology, San Raffaele Scientific Institute, Milano, Italy., De Palma C; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy.; Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, University Hospital 'Luigi Sacco', Milano, Italy., Giovarelli M; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy., Bizzozero L; Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.; Present address: Department of Oncology, Università degli Studi di Torino and Laboratory of Neurovascular Biology, Candiolo Cancer Institute, Candiolo, Italy., Pambianco S; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy., Di Renzo I; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy., Zecchini S; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy., Moscheni C; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy., Vantaggiato C; Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy., Procacci P; Department of Biomedical Sciences for Health (SCIBIS), Università degli Studi di Milano, Milano, Italy., Clementi E; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy.; Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.; Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, University Hospital 'Luigi Sacco', Milano, Italy., Perrotta C; Department of Biomedical and Clinical Sciences 'Luigi Sacco' (DIBIC), Università degli Studi di Milano, Milano, Italy.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2016 May 03; Vol. 7 (18), pp. 24995-5009.
DOI:	10.18632/oncotarget.8735
Abstrakt:	The sphingolipid metabolising enzyme Acid Sphingomyelinase (A-SMase) has been recently shown to inhibit melanoma progression and correlate inversely to tumour grade. In this study we have investigated the role of A-SMase in the chemo-resistance to anticancer treatmentusing mice with melanoma allografts and melanoma cells differing in terms of expression/activity of A-SMase. Since autophagy is emerging as a key mechanism in tumour growth and chemo-resistance, we have also investigated whether an action of A-SMase in autophagy can explain its role. Melanoma sensitivity to chemotherapeutic agent cisplatin in terms of cell viability/apoptosis, tumour growth, and animal survival depended directly on the A-SMase levels in tumoural cells. A-SMase action was due to inhibition of autophagy through activation of Akt/mammalian target of rapamycin (mTOR) pathway. Treatment of melanoma-bearing mice with the autophagy inhibitor chloroquine restored sensitivity to cisplatin of tumours expressing low levels of A-SMase while no additive effects were observed in tumours characterised by sustained A-SMase levels. The fact that A-SMase in melanomas affects mTOR-regulated autophagy and plays a central role in cisplatin efficacy encourages pre-clinical testing on the modulation of A-SMase levels/activity as possible novel anti-neoplastic strategy. Competing Interests: The authors declare they have no known conflicts of interest in this work.
Databáze:	MEDLINE
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