Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway

L. Bizzozero, D. Cazzato, D. Cervia, E. Assi, F. Simbari, F. Pagni, C. De Palma, A. Monno, C. Verdelli, P. R. Querini, V. Russo, E. Clementi, C. Perrotta

Research output: Contribution to journalArticlepeer-review

Abstract

Melanoma is a rapidly growing and highly metastatic cancer with high mortality rates, for which a resolutive treatment is lacking. Identification of novel therapeutic strategies and biomarkers of tumour stage is thus of particular relevance. We report here on a novel biomarker and possible candidate therapeutic target, the sphingolipid metabolising enzyme acid sphingomyelinase (A-SMase). A-SMase expression correlates inversely with tumour stage in human melanoma biopsies. Studies in a mouse model of melanoma and on cell lines derived from mouse and human melanomas demonstrated that A-SMase levels of expression actually determine the malignant phenotype of melanoma cells in terms of pigmentation, tumour progression, invasiveness and metastatic ability. The action of A-SMase is mediated by the activation of the extracellular signal-regulated kinase, the subsequent proteasomal degradation of the Microphtalmia-associated transcription factor (Mitf) and inhibition of cyclin-dependent kinase 2, Bcl-2 and c-Met, downstream targets of Mitf involved in tumour cell proliferation, survival and metastatisation.

Original languageEnglish
Pages (from-to)507-520
Number of pages14
JournalCell Death and Differentiation
Volume21
Issue number4
DOIs
Publication statusPublished - Apr 2014

Keywords

  • acid sphingomyelinase
  • melanoma
  • microphtalmia- associated transcription factor
  • signalling mechanisms

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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