Oncotarget

Research Papers: Autophagy and Cell Death:

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

Davide Cervia, Emma Assi, Clara De Palma, Matteo Giovarelli, Laura Bizzozero, Sarah Pambianco, Ilaria Di Renzo, Silvia Zecchini, Claudia Moscheni, Chiara Vantaggiato, Patrizia Procacci, Emilio Clementi and Cristiana Perrotta _

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Oncotarget. 2016; 7:24995-25009. https://doi.org/10.18632/oncotarget.8735

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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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