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

Abstract

// Davide Cervia 1,2 , Emma Assi 3,4 , Clara De Palma 2,5 , Matteo Giovarelli 2 , Laura Bizzozero 3,6 , Sarah Pambianco 2 , Ilaria Di Renzo 2 , Silvia Zecchini 2 , Claudia Moscheni 2 , Chiara Vantaggiato 3 , Patrizia Procacci 7 , Emilio Clementi 2,3,5 and Cristiana Perrotta 2 1 Department for Innovation in Biological, Agro-food and Forest Systems (DIBAF), Università degli Studi della Tuscia, Viterbo, Italy 2 Department of Biomedical and Clinical Sciences “Luigi Sacco” (DIBIC), Università degli Studi di Milano, Milano, Italy 3 Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy 4 Present address: Division of Experimental Oncology, San Raffaele Scientific Institute, Milano, Italy 5 Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, University Hospital “Luigi Sacco”, Milano, Italy 6 Present address: Department of Oncology, Università degli Studi di Torino and Laboratory of Neurovascular Biology, Candiolo Cancer Institute, Candiolo, Italy 7 Department of Biomedical Sciences for Health (SCIBIS), Università degli Studi di Milano, Milano, Italy Correspondence to: Cristiana Perrotta, email: // Emilio Clementi, email: // Keywords : A-SMase, melanoma, autophagy, mTOR, chemo-resistance Received : October 05, 2015 Accepted : March 28, 2016 Published : April 14, 2016 Abstract 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.