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.
Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin / D. Cervia, E. Assi, C. De Palma, M. Giovarelli, L. Bizzozero, S. Pambianco, I. Di Renzo, S. Zecchini, C. Moscheni, C. Vantaggiato, P. Procacci, E. Clementi, C. Perrotta. - In: ONCOTARGET. - ISSN 1949-2553. - 7:18(2016 May 01), pp. 24995-25009.
|Titolo:||Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin|
ASSI, EMMA (Secondo)
CLEMENTI, EMILIO GIUSEPPE IGNAZIO (Penultimo)
PERROTTA, CRISTIANA (Ultimo)
|Parole Chiave:||A-SMase; autophagy; chemo-resistance; mTOR; melanoma|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||1-mag-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.18632/oncotarget.8735|
|Appare nelle tipologie:||01 - Articolo su periodico|