Research Papers: Autophagy and Cell Death:
Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin
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Abstract
Davide Cervia1,2, Emma Assi3,4, Clara De Palma2,5, Matteo Giovarelli2, Laura Bizzozero3,6, Sarah Pambianco2, Ilaria Di Renzo2, Silvia Zecchini2, Claudia Moscheni2, Chiara Vantaggiato3, Patrizia Procacci7, Emilio Clementi2,3,5 and Cristiana Perrotta2
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.
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PII: 8735