Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin.
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.
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.
Davide
D
Cervia
Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.|Present address: Division of Experimental Oncology, San Raffaele Scientific Institute, Milano, Italy.
Emma
E
Assi
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.
Clara
C
De Palma
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.
Matteo
M
Giovarelli
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.
Laura
L
Bizzozero
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.
Sarah
S
Pambianco
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.
Ilaria
I
Di Renzo
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.
Silvia
S
Zecchini
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.
Claudia
C
Moscheni
Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.
Chiara
C
Vantaggiato
Department of Biomedical Sciences for Health (SCIBIS), Università degli Studi di Milano, Milano, Italy.
Patrizia
P
Procacci
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.
Emilio
E
Clementi
Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milano, Italy.
Cristiana
C
Perrotta
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D058570:TOR Serine-Threonine Kinases; D013108:Sphingomyelin Phosphodiesterase; D002945:Cisplatin
A-SMase; autophagy; chemo-resistance; mTOR; melanoma