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

• Published in: Cell death and differentiation Vol. 21; no. 4; pp. 507 - 520
• Main Authors: Bizzozero, L, Cazzato, D, Cervia, D, Assi, E, Simbari, F, Pagni, F, De Palma, C, Monno, A, Verdelli, C, Querini, P R, Russo, V, Clementi, E, Perrotta, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2014; Nature Publishing Group
• Subjects: 631/67/1813/1634; 631/67/322; 631/80/82/23; 631/80/86; Acids; Animals; Apoptosis; Biochemistry; Biomarkers; Biomedical and Life Sciences; Biopsy; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cloning; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinases; Disease Progression; Down-Regulation; Enzymes; Female; Genotype & phenotype; Humans; Kinases; Life Sciences; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lymphatic system; Medical prognosis; Melanoma; Melanoma - metabolism; Melanoma - pathology; Melanoma, Experimental - metabolism; Melanoma, Experimental - mortality; Melanoma, Experimental - pathology; Metastasis; Mice; Mice, Inbred C57BL; Microphthalmia-Associated Transcription Factor - metabolism; Original Paper; Pigmentation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-met - metabolism; Signal Transduction; Skin cancer; Sphingomyelin Phosphodiesterase - antagonists & inhibitors; Sphingomyelin Phosphodiesterase - genetics; Sphingomyelin Phosphodiesterase - metabolism; Stem Cells; Transcription factors; Italy; melanoma; signalling mechanisms; microphtalmia-associated transcription factor; acid sphingomyelinase
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.173

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.