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, Cristiana Perrotta

Research output: Contribution to journalArticlepeer-review

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 treatment using 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.

Original languageEnglish
Pages (from-to)24995-25009
Number of pages15
JournalOncotarget
Volume7
Issue number18
DOIs
Publication statusPublished - May 1 2016

Keywords

  • A-SMase
  • Autophagy
  • Chemo-resistance
  • Melanoma
  • mTOR

ASJC Scopus subject areas

  • Oncology

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