title: Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway.
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.
authors: Scientific Institute IRCCS E Medea, Bosisio Parini, Lecco, Italy.
authors: L
authors: L
authors: Bizzozero
authors: 1] Scientific Institute IRCCS E Medea, Bosisio Parini, Lecco, Italy [2] Unit of Clinical Pharmacology, National Research Council Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Università di Milano, Milan, Italy.
authors: D
authors: D
authors: Cazzato
authors: 1] Unit of Clinical Pharmacology, National Research Council Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Università di Milano, Milan, Italy [2] Department for Innovation in Biological, Agro-food and Forest systems, Università della Tuscia, Viterbo, Italy.
authors: D
authors: D
authors: Cervia
authors: Unit of Clinical Pharmacology, National Research Council Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Università di Milano, Milan, Italy.
authors: E
authors: E
authors: Assi
authors: Research Unit on Bioactive Molecules, Department of Biomedical Chemistry, Institute for Advanced Chemistry of Catalonia, Spanish Council for Scientific Research (IQAC-CSIC), Barcelona, Spain.
authors: F
authors: F
authors: Simbari
authors: Department of Pathology, Università di Milano-Bicocca, Monza, Italy.
authors: F
authors: F
authors: Pagni
authors: Unit of Clinical Pharmacology, National Research Council Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Università di Milano, Milan, Italy.
authors: C
authors: C
authors: De Palma
authors: Division of Regenerative Medicine and Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: A
authors: A
authors: Monno
authors: Unit of Clinical Pharmacology, National Research Council Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Università di Milano, Milan, Italy.
authors: C
authors: C
authors: Verdelli
authors: Division of Regenerative Medicine and Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: P R
authors: PR
authors: Querini
authors: Division of Regenerative Medicine and Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: V
authors: V
authors: Russo
authors: 1] Scientific Institute IRCCS E Medea, Bosisio Parini, Lecco, Italy [2] Unit of Clinical Pharmacology, National Research Council Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Università di Milano, Milan, Italy.
authors: E
authors: E
authors: Clementi
authors: Unit of Clinical Pharmacology, National Research Council Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Università di Milano, Milan, Italy.
authors: C
authors: C
authors: Perrotta
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D010858:Pigmentation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D019859:Proto-Oncogene Proteins c-met; D051357:Cyclin-Dependent Kinase 2; C577975:ASMase, mouse; D013108:Sphingomyelin Phosphodiesterase